Concentrated liquid pharmaceutical formulations of furosemide

ABSTRACT

Disclosed herein, in part, are liquid pharmaceutical formulations comprising furosemide or a pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable excipients, and a pharmaceutically acceptable buffer. Methods of treating congestion, edema, fluid overload, or hypertension in a patient in need thereof are also provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.17/426,765, filed on Jul. 29, 2021, which application is a U.S. nationalstage patent application under 35 U.S.C. § 371 of InternationalApplication No. PCT/US2020/015799, filed on Jan. 30, 2020, which claimsthe benefit of, and priority to, U.S. Patent Application No. 62/799,215,filed on Jan. 31, 2019, the content of each of which is herebyincorporated by reference in its entirety.

BACKGROUND

Furosemide, an exemplary loop diuretic, can be used in the treatment ofhypertension, edema and related conditions, including decompensatedheart failure. Furosemide is commonly used in the treatment and/ormanagement of edema associated with cardiac, renal, and hepaticinsufficiency or failure, for example, congestive heart failure. H.Bundgaard, T. Norgaard, N. M. Nielsen, “Photodegradation and hydrolysisof furosemide and furosemide esters in aqueous solutions,” InternationalJournal of Pharmaceutics 42, 217 (1988).

Oral bioavailability, and therefore oral efficacy, of furosemide islimited. Furosemide is commonly administered both parenterally andorally, although highly variable oral absorption is observed due to thecombined effects of limited solubility and decreased stability at acidicpH. B. Devarakonda, D. P. Otto, A. Judefeind, R. A. Hill, M. M. deVilliers, “Effect of pH on the solubility and release of furosemide frompolyamidoamine (PAMAM) dendrimer complexes,” International Journal ofPharmaceutics 345, 142 (Dec. 10, 2007). Accordingly, furosemidetypically is administered intravenously or intramuscularly for mostpatients with decompensated heart failure or other forms of moreadvanced edema.

Intravenous administration of a pharmaceutical drug, such as furosemide,requires a trained healthcare professional for placement of the catheterand administration of the drug solution. In contrast, subcutaneousadministration of a pharmaceutical drug can be accomplished with the aidof auto-injection devices and/or minipumps or subcutaneous injections orinfusions, which can permit administration to be performed by thepatient or caregiver, for example, at home. Subcutaneous administrationof furosemide by the patient or caregiver also can allow for moreoptimal therapeutic administration and total dose to provide a moreappropriate pharmacokinetic and pharmacodynamic profile and patientoutcome.

For subcutaneous administration, discomfort and pain duringadministration should be minimized so as to avoid poor patientcompliance with the treatment regimen. Factors that can contribute topain and discomfort perceived by a patient upon, during, or aftersubcutaneous administration include the injection volume, the pH of theformulation, and the osmoticity or tonicity of the formulation.Moreover, such a formulation should be stable in solution so that itreadily is available for use and/or can be pre-loaded into a variety ofdispensing devices.

Therefore, a need exists for improved pharmaceutical formulationscontaining furosemide that contain a sufficient concentration offurosemide, and are at an appropriate pH and osmolality, for example, topermit subcutaneous administration of furosemide.

SUMMARY

In one aspect, the invention provides a liquid pharmaceuticalformulation of furosemide or a pharmaceutically acceptable salt thereof.

In various embodiments of the invention, the liquid pharmaceuticalformulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) one or more pharmaceutically acceptable excipients; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL. In certainembodiments, the pH of the liquid pharmaceutical formulation is fromabout 6.5 to about 8.5.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 30% (w/w) of one or more        pharmaceutically acceptable excipients selected from the group        consisting of ethanol, benzyl alcohol, glycerin,        N-methyl-pyrrolidone (NMP), sodium chloride, a polyethylene        glycol (PEG), propylene glycol, a polysorbate, a        polyvinylpyrrolidone (PVP), a cyclodextrin, and any combination        thereof; and    -   (iii) from about 25 mM to about 500 mM of a pharmaceutically        acceptable buffer selected from the group consisting of        histidine, a citrate salt, sodium phosphate, potassium        phosphate, tromethamine or a pharmaceutically acceptable salt        thereof, and any combination thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL and the pH of the liquid pharmaceutical formulation is        from about 6.5 to about 8.5.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) N-methyl-pyrrolidone (NMP); and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol;

(iii) N-methyl-pyrrolidone (NMP); and

(iv) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In certain embodiments of the invention, the liquid pharmaceuticalformulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) from about 0.1% (w/w) to about 10% (w/w) N-methyl-pyrrolidone;

(iii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol; and

(iv) from about 25 mM to about 250 mM tromethamine or a pharmaceuticallyacceptable salt thereof,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In another aspect, the invention provides a unit liquid pharmaceuticalformulation of furosemide or a pharmaceutically acceptable salt thereof.

In certain embodiments of the invention, the unit liquid pharmaceuticalformulation comprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 30% (w/w) of one or more        pharmaceutically acceptable excipients selected from the group        consisting of ethanol, benzyl alcohol, glycerin,        N-methyl-pyrrolidone (NMP), sodium chloride, a polyethylene        glycol (PEG), propylene glycol, a polysorbate, a        polyvinylpyrrolidone (PVP), a cyclodextrin, and any combination        thereof; and    -   (iii) from about 25 mM to about 500 mM of a pharmaceutically        acceptable buffer selected from the group consisting of        histidine, a citrate salt, sodium phosphate, potassium        phosphate, tromethamine or a pharmaceutically acceptable salt        thereof, and any combination thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL and wherein the pH of the liquid pharmaceutical        formulation is from about 6.5 to about 8.5.

In certain embodiments of the invention, the unit liquid pharmaceuticalformulation comprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 200        mg/mL.

In certain embodiments of the invention, the unit liquid pharmaceuticalformulation comprises:

(i) from about 10 mg to about 200 mg furosemide, or a pharmaceuticallyacceptable salt thereof;

(ii) from about 0.1% (w/w) to about 10% (w/w) N-methyl-pyrrolidone;

(iii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol; and

(iv) from about 25 mM to about 250 mM tromethamine or a pharmaceuticallyacceptable salt thereof,

wherein the concentration of furosemide in the unit liquidpharmaceutical formulation is from about 40 mg/mL to about 200 mg/mL.

In certain embodiments, the liquid pharmaceutical formulation or theunit liquid pharmaceutical formulation comprises one of more of water; apH adjuster; and an osmolarity adjuster.

Another aspect of the invention provides a method of treatingcongestion, edema, fluid overload, or hypertension in a patient in needthereof, the method comprising administering to the patient a liquidpharmaceutical formulation or a unit liquid pharmaceutical formulationdescribed herein.

Another aspect of the invention provides a kit for the treatment ofcongestion, edema, fluid overload, or hypertension comprising a liquidpharmaceutical formulation or a unit liquid pharmaceutical formulationdescribed herein.

DETAILED DESCRIPTION

The invention provides liquid pharmaceutical formulations and unitliquid pharmaceutical formulations containing furosemide, medical kitscontaining the same, and methods of using the liquid pharmaceuticalformulations and unit liquid pharmaceutical formulations to treatmedical disorders e.g., congestion, edema, fluid overload, orhypertension in a patient in need thereof. In particular, the inventioncan provide pharmaceutical formulations including an increasedconcentration of furosemide, or a pharmaceutically acceptable saltthereof, using one or more pharmaceutically acceptable excipients alongwith a pharmaceutically acceptable buffer, which can maintain anappropriate pH for administration to a patient.

Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. The abbreviations used hereinhave their conventional meaning within the chemical and biological arts.The chemical structures and formulae set forth herein are constructedaccording to the standard rules of chemical valency known in thechemical arts.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components.

Further, it should be understood that elements and/or features of acomposition or a method described herein can be combined in a variety ofways without departing from the spirit and scope of the presentinvention, whether explicit or implicit herein. For example, wherereference is made to a particular compound, that compound can be used invarious embodiments of compositions of the present invention and/or inmethods of the present invention, unless otherwise understood from thecontext. In other words, within this application, embodiments have beendescribed and depicted in a way that enables a clear and conciseapplication to be written and drawn, but it is intended and will beappreciated that embodiments may be variously combined or separatedwithout parting from the present teachings and invention(s). Forexample, it will be appreciated that all features described and depictedherein can be applicable to all aspects of the invention(s) describedand depicted herein.

It should be understood that the expression “at least one of” includesindividually each of the recited objects after the expression and thevarious combinations of two or more of the recited objects unlessotherwise understood from the context and use. The expression “and/or”in connection with three or more recited objects should be understood tohave the same meaning unless otherwise understood from the context.

The use of the term “include,” “includes,” “including,” “have,” “has,”“having,” “contain,” “contains,” or “containing,” including grammaticalequivalents thereof, should be understood generally as open-ended andnon-limiting, for example, not excluding additional unrecited elementsor steps, unless otherwise specifically stated or understood from thecontext.

Where the use of the term “about” is before a quantitative value, thepresent invention also includes the specific quantitative value itself,unless specifically stated otherwise. As used herein, the term “about”refers to a ±10% variation from the nominal value unless otherwiseindicated or inferred from the context.

At various places in the present specification, values are disclosed ingroups or in ranges. It is specifically intended that the descriptioninclude each and every individual subcombination of the members of suchgroups and ranges. For example, an integer in the range of 0 to 40 isspecifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and aninteger in the range of 1 to 20 is specifically intended to individuallydisclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, and 20.

The use of any and all examples, or exemplary language herein, forexample, “such as” or “including,” is intended merely to illustratebetter the present invention and does not pose a limitation on the scopeof the invention unless claimed. No language in the specification shouldbe construed as indicating any non-claimed element as essential to thepractice of the present invention.

As used herein, a “compound” (including a specifically named compound,e.g., furosemide) refers to the compound itself and its pharmaceuticallyacceptable salts unless otherwise understood from the context of thedescription or expressly limited to one particular form of the compound,e.g., the compound itself, or a pharmaceutically acceptable saltthereof.

As used herein, “furosemide” refers to a compound having the formula:

and pharmaceutically acceptable salts thereof. Such salts may include,but are not limited to, furosemide sodium salt and furosemide quaternaryammonium salt. Furosemide may be referred to by other names, forexample, frusemide,5-(aminosulphonyl)-4-chloro-2-[(2-furanyl-methyl)amino]benzoic acid, orits IUPAC name, 4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoyl-benzoicacid, or its common trade name, Lasix®.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods and/or compositions described herein. Suchorganisms are preferably mammals (e.g., murines, simians, equines,bovines, porcines, canines, felines, and the like), and more preferablyhumans.

As used herein, a “buffer” refers to an aqueous solution that isresistant to changes in pH. A buffer may include a “buffering agent”such as a weak acid and its salt, or a weak base and its salt, whichassist in maintaining the stability of the pH. Examples of buffers usedin pharmaceutical formulations include bicarbonate buffers, carbonatebuffers, citrate buffers, histidine buffers, phosphate buffers, tartratebuffers, tris(hydroxymethyl)aminomethane (or2-amino-2-hydroxymethyl-propane-1,3-diol [(HOCH₂)₃CNH₂]) buffers, andcombinations thereof. Certain of these buffers are suitable forpharmaceutical formulations administered subcutaneously.

Tris(hydroxymethyl)aminomethane or a tris(hydroxymethyl)aminomethanebuffer can be referred to as “TRIS,” “Tris,” “Tris buffer,” “Trisamine,”“THAM,” “tromethamine,” and other names. In addition, many buffersand/or buffer systems can include Tris, or a pharmaceutically acceptablesalt thereof, and can be used in the present teachings. For example,Tris-buffered saline (“TBS”), Tris-hydrochloride buffer (“Tris-HCl”),Tris base (pH 10.6), Tris/borate/ethylene diamine tetra-acetate (“EDTA”)buffer (“TBE”), and Tris/acetate/EDTA buffer (“TAE”). Tris base often isused with Tris-HCl to prepare Tris buffers at a desired pH. In addition,the present teachings can include Tris-related compounds, for example,compounds derived from Tris or structurally-related to Tris, that canact as a buffer.

As used herein, “tonicity” refers to the ionic strength or concentrationof ions in a solution such as a pharmaceutical formulation. Tonicityoften is measured in molarity (“M”). As used herein, an “isotonicsolution,” an “isotonic formulation,” an “isotonic pharmaceuticalformulation,” and a pharmaceutical formulation that is “isotonic” refersto a solution or formulation that has the same or similar concentrationof ions as found in bodily fluids.

As used herein, “physiological pH” refers to a pH of about 7.4.

As used herein, “osmoticity” and “osmolality” refer to the osmoticpressure of a solution such as a pharmaceutical formulation. Osmoticityoften is measured in osmolarity (“Osm/L” or “OsM”) or osmolality(“Osm/kg”), which can be used interchangeably herein. When measuringfreezing point depression, the observed value is the osmolality of thesolution. In contrast to tonicity, osmoticity accounts for un-ionizedsolutes in a solution such that when present, the osmolarity orosmolality of the solution will be higher than its tonicity. Theosmolarity of a liquid pharmaceutical formulation described herein canbe measured, for example, using a vapor pressure method.

As used herein, an “isosmotic solution,” an “isosmotic formulation,” an“isosmotic pharmaceutical formulation,” and a pharmaceutical formulationthat is “isosmotic” refers to a solution or a formulation that has thesame or similar concentration of solutes as found in bodily fluids. Incertain embodiments, a liquid pharmaceutical formulation that is“isosmotic” can have an osmolarity in the range of about 275 mOsM toabout 350 mOsM or when the osmolality of the formulation is in the rangeof about 275 mOsm/kg to about 350 mOsm/kg.

As used herein, “osmolarity adjustor” and “osmotic agent” refer to apharmaceutically acceptable compound that may be added to a liquidpharmaceutical formulation described herein in order to modulate theosmolarity of the liquid pharmaceutical formulation.

As used herein, “pharmaceutically acceptable” refers to a substance thatis acceptable for use in pharmaceutical applications from atoxicological perspective and does not adversely interact with theactive ingredient. Accordingly, pharmaceutically acceptable carriers arethose that are compatible with the other ingredients in the formulationand are biologically acceptable. In certain embodiments, supplementaryactive ingredients can also be incorporated into the pharmaceuticalcompositions.

As used herein, “pharmaceutically acceptable excipient” refers to asubstance that aids the administration of an active agent to andabsorption by a subject and can be included in the compositions of thepresent invention without causing a significant adverse toxicologicaleffect on the patient. Non-limiting examples of pharmaceuticallyacceptable excipients include water, NaCl, normal saline solutions, aphosphate buffered saline solution, emulsions (e.g., such as anoil/water or water/oil emulsions), lactated Ringer's, normal sucrose,normal glucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with the compounds of the invention. Forexamples of excipients and carriers, see Martin, Remington'sPharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. (1975).

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin, Remington'sPharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

As used herein, the term “effective amount” refers to the amount of acomposition (e.g., a liquid pharmaceutical formulation of the presentinvention) sufficient to effect beneficial or desired results. Aneffective amount can be administered in one or more administrations,applications or dosages and is not intended to be limited to aparticular formulation or administration route.

As used herein, the terms “treat,” “treating,” and “treatment” includeany effect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

The phrase “therapeutically-effective amount” as used herein means thatamount of a composition (e.g., a liquid pharmaceutical formulation ofthe present invention) which is effective for producing some desiredtherapeutic effect in a subject.

As used herein, the term “congestion” (in heart failure) is the presenceof signs and symptoms of extracellular fluid accumulation that resultsin increased cardiac filling pressures leading to reduced cardiacoutput. This reduced cardiac output is further exacerbated byneurohormonal activation leading to increased renal sodium and wateravidity resulting in an increased plasma volume.

As used herein, “fluid overload,” “volume overload” and “hypervolemia”,may describe a medical condition where there is too much fluid in theblood. Excess fluid, primarily salt and water, may build up throughoutthe body resulting in weight gain.

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

Liquid Pharmaceutical Formulations of Furosemide

As described herein, in one aspect, the invention provides liquidpharmaceutical formulations of furosemide or a pharmaceuticallyacceptable salt thereof.

In various embodiments, a liquid pharmaceutical formulation generallycomprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) one or more pharmaceutically acceptable excipients; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In various embodiments, the one or more pharmaceutically acceptableexcipients is selected from the group consisting of ethanol, benzylalcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, apolyethylene glycol (PEG), propylene glycol, a polysorbate, apolyvinylpyrrolidone (PVP), a cyclodextrin, and any combination thereof.In certain embodiments, the PEG has a weight average molecular weight offrom about 3000 g/mol to about 3700 g/mol. In certain embodiments, thepolysorbate is polysorbate 80. In certain embodiments, the PVP has aweight average molecular weight of about 4000 g/mol to about 6000 g/mol.In certain embodiments, the cyclodextrin is β-cyclodextrin.

In certain embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the liquid pharmaceutical formulationsdescribed herein can be from about 0.1% (w/w) to about 30% (w/w), fromabout 0.5% (w/w) to about 30% (w/w), from about 1% (w/w) to about 30%(w/w), from about 1.5% (w/w) to about 30% (w/w), (w/w), from about 2%(w/w) to about 30% (w/w), from about 2.5% (w/w) to about 30% (w/w), fromabout 3% (w/w) to about 30% (w/w), from about 3.5% (w/w) to about 30%(w/w), from about 4% (w/w) to about 30% (w/w), from about 4.5% (w/w) toabout 30% (w/w), from about 5% (w/w) to about 30% (w/w), from about 10%(w/w) to about 30% (w/w), from about 15% (w/w) to about 30% (w/w), fromabout 20% (w/w) to about 30% (w/w), from about 25% (w/w) to about 30%(w/w), from about 0.1% (w/w) to about 25% (w/w), from about 0.1% (w/w)to about 20% (w/w), from about 0.1% (w/w) to about 15% (w/w), from about0.1% (w/w) to about 10% (w/w), from about 0.1% (w/w) to about 5% (w/w),from about 0.1% (w/w) to about 4.5% (w/w), from about 0.1% (w/w) toabout 4% (w/w), from about 0.1% (w/w) to about 3.5% (w/w), from about0.1% (w/w) to about 3% (w/w), from about 0.1% (w/w) to about 2.5% (w/w),from about 0.1% (w/w) to about 2% (w/w), from about 0.1% (w/w) to about1.5% (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1%(w/w) to about 0.5% (w/w), from about 0.5% (w/w) to about 25% (w/w),from about 0.5% (w/w) to about 20% (w/w), from about 0.5% (w/w) to about15% (w/w), from about 0.5% (w/w) to about 10% (w/w), from about 0.5%(w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4.5% (w/w), fromabout 0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3.5%(w/w), from about 0.5% (w/w) to about 3% (w/w), from about 0.5% (w/w) toabout 2.5% (w/w), from about 0.5% (w/w) to about 2% (w/w), from about0.5% (w/w) to about 1.5% (w/w), from about 0.5% (w/w) to about 1% (w/w),from about 1% (w/w) to about 25% (w/w), from about 1% (w/w) to about 20%(w/w), from about 1% (w/w) to about 15% (w/w), from about 1% (w/w) toabout 10% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1%(w/w) to about 4.5% (w/w), from about 1% (w/w) to about 4% (w/w), fromabout 1% (w/w) to about 3.5% (w/w), from about 1% (w/w) to about 2.5%(w/w), from about 1% (w/w) to about 2% (w/w), from about 1% (w/w) toabout 1.5% (w/w), from about 1.5% (w/w) to about 25% (w/w), from about1.5% (w/w) to about 20% (w/w), from about 1.5% (w/w) to about 15% (w/w),from about 1.5% (w/w) to about 10% (w/w), from about 1.5% (w/w) to about5% (w/w), from about 1.5% (w/w) to about 4.5% (w/w), from about 1.5%(w/w) to about 4% (w/w), from about 1.5% (w/w) to about 3.5% (w/w), fromabout 1.5% (w/w) to about 3% (w/w), from about 1.5% (w/w) to about 2.5%(w/w), from about 1.5% (w/w) to about 2% (w/w), from about 2% (w/w) toabout 25% (w/w), from about 2% (w/w) to about 20% (w/w), from about 2%(w/w) to about 15% (w/w), from about 2% (w/w) to about 10% (w/w), fromabout 2% (w/w) to about 5% (w/w), from about 2% (w/w) to about 4.5%(w/w), from about 2% (w/w) to about 4% (w/w), from about 2% (w/w) toabout 3.5% (w/w), from about 2% (w/w) to about 3% (w/w), from about 2%(w/w) to about 2.5% (w/w), from about 2.5% (w/w) to about 25% (w/w),from about 2.5% (w/w) to about 20% (w/w), from about 2.5% (w/w) to about15% (w/w), from about 2.5% (w/w) to about 10% (w/w), from about 2.5%(w/w) to about 5% (w/w), from about 2.5% (w/w) to about 4.5% (w/w), fromabout 2.5% (w/w) to about 4% (w/w), from about 2.5% (w/w) to about 3.5%(w/w), from about 2.5% (w/w) to about 3% (w/w), from about 3% (w/w) toabout 25% (w/w), from about 3% (w/w) to about 20% (w/w), from about 3%(w/w) to about 15% (w/w), from about 3% (w/w) to about 10% (w/w), fromabout 3% (w/w) to about 5% (w/w), from about 3% (w/w) to about 4.5%(w/w), from about 3% (w/w) to about 4% (w/w), from about 3% (w/w) toabout 3.5% (w/w), from about 3.5% (w/w) to about 25% (w/w), from about3.5% (w/w) to about 20% (w/w), from about 3.5% (w/w) to about 15% (w/w),from about 3.5% (w/w) to about 10% (w/w), from about 3.5% (w/w) to about5% (w/w), from about 3.5% (w/w) to about 4.5% (w/w), from about 3.5%(w/w) to about 4% (w/w), from about 4% (w/w) to about 25% (w/w), fromabout 4% (w/w) to about 20% (w/w), from about 4% (w/w) to about 15%(w/w), from about 4% (w/w) to about 10% (w/w), from about 4% (w/w) toabout 5% (w/w), from about 4% (w/w) to about 4.5% (w/w), from about 4.5%(w/w) to about 25% (w/w), from about 4.5% (w/w) to about 20% (w/w), fromabout 4.5% (w/w) to about 15% (w/w), from about 4.5% (w/w) to about 10%(w/w), from about 4.5% (w/w) to about 5% (w/w), from about 5% (w/w) toabout 25% (w/w), from about 5% (w/w) to about 20% (w/w), from about 5%(w/w) to about 15% (w/w), from about 5% (w/w) to about 10% (w/w), fromabout 10% (w/w) to about 25% (w/w), from about 10% (w/w) to about 20%(w/w), from about 10% (w/w) to about 15% (w/w), from about 15% (w/w) toabout 25% (w/w), from about 15% (w/w) to about 20% (w/w), or from about20% (w/w) to about 25% (w/w). In certain embodiments, the amount of theone or more pharmaceutically acceptable excipients in the liquidpharmaceutical formulation is from about 1.5% (w/w) to about 30% (w/w).In certain embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the liquid pharmaceutical formulation is fromabout 5% (w/w) to about 15% (w/w). In certain embodiments, the amount ofthe one or more pharmaceutically acceptable excipients in the liquidpharmaceutical formulation is from about 0.1% (w/w) to about 10% (w/w).In certain embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the liquid pharmaceutical formulation is fromabout 0.5% (w/w) to about 5% (w/w).

In various embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the liquid pharmaceutical formulationsdescribed herein can about 0.1% (w/w), about 0.25% (w/w), about 0.5%(w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5%(w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5%(w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w),about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17%(w/w), about 18% (w/w), about 19% (w/w), about 20% (w/w), about 21%(w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25%(w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29%(w/w), or about 30% (w/w).

In certain embodiments, the one or more pharmaceutically acceptableexcipients comprises benzyl alcohol. In certain embodiments, the one ormore pharmaceutically acceptable excipients comprises NMP. In certainembodiments, the one or more pharmaceutically acceptable excipientscomprises NMP and benzyl alcohol.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In certain embodiments, the liquid pharmaceutical formulation furthercomprises N-methyl-pyrrolidone (NMP).

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol;

(iii) N-methyl-pyrrolidone (NMP); and

(iv) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In various embodiments, the amount of benzyl alcohol in the liquidpharmaceutical formulations described herein can be from about 0.1%(w/w) to about 10% (w/w), from about 0.5% (w/w) to about 10% (w/w), fromabout 1% (w/w) to about 10% (w/w), from about 2% (w/w) to about 10%(w/w), from about 3% (w/w) to about 10% (w/w), from about 4% (w/w) toabout 10% (w/w), from about 5% (w/w) to about 10% (w/w), from about 0.1%(w/w) to about 5% (w/w), from about 0.1% (w/w) to about 4% (w/w), fromabout 0.1% (w/w) to about 3% (w/w), from about 0.1% (w/w) to about 2%(w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1% (w/w) toabout 0.5% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w),from about 0.5% (w/w) to about 2% (w/w), from about 0.5% (w/w) to about1% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1% (w/w) toabout 4% (w/w), from about 1% (w/w) to about 3% (w/w), from about 1%(w/w) to about 2% (w/w), from about 2% (w/w) to about 5% (w/w), fromabout 2% (w/w) to about 4% (w/w), from about 2% (w/w) to about 3% (w/w),from about 3% (w/w) to about 5% (w/w), from about 3% (w/w) to about 4%(w/w), or from about 4% (w/w) to about 5% (w/w). In certain embodiments,the amount of benzyl alcohol in the liquid pharmaceutical formulation isfrom about 0.1% (w/w) to about 10% (w/w). In certain embodiments, theamount of benzyl alcohol in the liquid pharmaceutical formulation isfrom about 0.5% (w/w) to about 5% (w/w).

In various embodiments, the amount of benzyl alcohol in the liquidpharmaceutical formulations described herein can be about 0.1% (w/w),about 0.5% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w),about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w),about 4.5% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about8% (w/w), about 9% (w/w), or about 10% (w/w). In certain embodiments,the amount of benzyl alcohol in the liquid pharmaceutical formulation isabout 4% (w/w).

In various embodiments, the amount of NMP in the liquid pharmaceuticalformulations described herein can be from about 0.1% (w/w) to about 10%(w/w), from about 0.5% (w/w) to about 10% (w/w), from about 1% (w/w) toabout 10% (w/w), from about 2% (w/w) to about 10% (w/w), from about 3%(w/w) to about 10% (w/w), from about 4% (w/w) to about 10% (w/w), fromabout 5% (w/w) to about 10% (w/w), from about 0.1% (w/w) to about 5%(w/w), from about 0.1% (w/w) to about 4% (w/w), from about 0.1% (w/w) toabout 3% (w/w), from about 0.1% (w/w) to about 2% (w/w), from about 0.1%(w/w) to about 1% (w/w), from about 0.1% (w/w) to about 0.5% (w/w), fromabout 0.5% (w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4%(w/w), from about 0.5% (w/w) to about 3% (w/w), from about 0.5% (w/w) toabout 2% (w/w), from about 0.5% (w/w) to about 1% (w/w), from about 1%(w/w) to about 5% (w/w), from about 1% (w/w) to about 4% (w/w), fromabout 1% (w/w) to about 3% (w/w), from about 1% (w/w) to about 2% (w/w),from about 2% (w/w) to about 5% (w/w), from about 2% (w/w) to about 4%(w/w), from about 2% (w/w) to about 3% (w/w), from about 3% (w/w) toabout 5% (w/w), from about 3% (w/w) to about 4% (w/w), or from about 4%(w/w) to about 5% (w/w). In certain embodiments, the amount of NMP inthe liquid pharmaceutical formulation is from about 0.1% (w/w) to about10% (w/w). In certain embodiments, the amount of NMP in the liquidpharmaceutical formulation is from about 0.1% (w/w) to about 1% (w/w).

In various embodiments, the amount of NMP in the liquid pharmaceuticalformulations described herein can be about 0.1% (w/w), about 0.5% (w/w),about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w),about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w),about 5% (w/w), about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w),about 7% (w/w), about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w),about 9% (w/w), about 9.5% (w/w), or about 10% (w/w). In someembodiments, the amount of NMP in the liquid pharmaceutical formulationis about 0.5 (w/w).

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) N-methyl-pyrrolidone (NMP); and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL.

In various embodiments, the amount of NMP in the liquid pharmaceuticalformulations described herein can be from about 1% (w/w) to about 25%(w/w), from about 2.5% (w/w) to about 25% (w/w), from about 5% (w/w) toabout 25% (w/w), from about 7.5% (w/w) to about 25% (w/w), from about10% (w/w) to about 25% (w/w), from about 12.5% (w/w) to about 25% (w/w),from about 15% (w/w) to about 25% (w/w), from about 20% (w/w) to about25% (w/w), from about 1% (w/w) to about 20% (w/w), from about 1% (w/w)to about 15% (w/w), from about 1% (w/w) to about 12.5% (w/w), from about1% (w/w) to about 10% (w/w), from about 1% (w/w) to about 7.5% (w/w),from about 1% (w/w) to about 5% (w/w), from about 1% (w/w) to about 2.5%(w/w), from about 2.5% (w/w) to about 20% (w/w), from about 2.5% (w/w)to about 15% (w/w), from about 2.5% (w/w) to about 12.5% (w/w), fromabout 2.5% (w/w) to about 10% (w/w), from about 2.5% (w/w) to about 7.5%(w/w), from about 2.5% (w/w) to about 5% (w/w), from about 5% (w/w) toabout 20% (w/w), from about 5% (w/w) to about 15% (w/w), from about 5%(w/w) to about 12.5% (w/w), from about 5% (w/w) to about 10% (w/w), fromabout 5% (w/w) to about 7.5% (w/w), from about 7.5% (w/w) to about 20%(w/w), from about 7.5% (w/w) to about 15% (w/w), from about 7.5% (w/w)to about 12.5% (w/w), from about 7.5% (w/w) to about 10% (w/w), fromabout 10% (w/w) to about 20% (w/w), from about 10% (w/w) to about 15%(w/w), from about 10% (w/w) to about 12.5% (w/w), from about 12.5% (w/w)to about 20% (w/w), from about 12.5% (w/w) to about 15% (w/w), fromabout 12.5% (w/w) to about 20% (w/w), from about 12.5% (w/w) to about15% (w/w), or from about 15% (w/w) to about 20% (w/w). In certainembodiments, the amount of NMP in the liquid pharmaceutical formulationis from about 1% (w/w) to about 25% (w/w). In certain embodiments, theamount of NMP in the liquid pharmaceutical formulation is from about 5%(w/w) to about 10% (w/w).

In various embodiments, the amount of NMP in the liquid pharmaceuticalformulations described herein can be about 1% (w/w), about 1.5% (w/w),about 2% (w/w), about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w),about 4% (w/w), about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w),about 6% (w/w), about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w),about 8% (w/w), about 8.5% (w/w), about 9% (w/w), about 9.5% (w/w),about 10% (w/w), about 12.5% (w/w), about 15% (w/w), about 20% (w/w), orabout 25% (w/w).

In certain embodiments, the liquid pharmaceutical formulation furthercomprises benzyl alcohol.

In various embodiments, the amount of benzyl alcohol in the liquidpharmaceutical formulations described herein can be from about 0.5%(w/w) to about 5% (w/w), from about 1% (w/w) to about 5% (w/w), fromabout 2% (w/w) to about 5% (w/w), from about 3% (w/w) to about 5% (w/w),from about 4% (w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4%(w/w), from about 0.5% (w/w) to about 3% (w/w), from about 0.5% (w/w) toabout 2% (w/w), from about 0.5% (w/w) to about 1% (w/w), from about 1%(w/w) to about 4% (w/w), from about 1% (w/w) to about 3% (w/w), fromabout 1% (w/w) to about 2% (w/w), from about 2% (w/w) to about 4% (w/w),from about 2% (w/w) to about 3% (w/w), or from about 3% (w/w) to about4% (w/w). In certain embodiments, the amount of benzyl alcohol in theliquid pharmaceutical formulation is from about 0.5% (w/w) to about 5%(w/w). In certain embodiments, the amount of benzyl alcohol in theliquid pharmaceutical formulation is from about 1% (w/w) to about 3%(w/w).

In various embodiments, the amount of benzyl alcohol in the liquidpharmaceutical formulations described herein can be about 0.5% (w/w),about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w),about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), orabout 5% (w/w).

In various embodiments, the concentration of the pharmaceuticallyacceptable buffer in the liquid pharmaceutical formulations describedherein can be from about 25 mM to about 500 mM, from about 30 mM toabout 500 mM, from about 40 mM to about 500 mM, from about 50 mM toabout 500 mM, from about 75 mM to about 500 mM, from about 100 mM toabout 500 mM, from about 150 mM to about 500 mM, from about 200 mM toabout 500 mM, from about 200 mM to about 500 mM, from about 250 mM toabout 500 mM, from about 300 mM to about 500 mM, from about 350 mM toabout 500 mM, from about 400 mM to about 500 mM, from about 450 mM toabout 500 mM, from about 25 mM to about 450 mM, from about 25 mM toabout 400 mM, from about 25 mM to about 350 mM, from about 25 mM toabout 300 mM, from about 25 mM to about 250 mM, from about 25 mM toabout 200 mM, from about 25 mM to about 150 mM, from about 25 mM toabout 100 mM, from about 25 mM to about 75 mM, from about 25 mM to about50 mM, from about 25 mM to about 40 mM, from about 25 mM to about 30 mM,from about 30 mM to about 450 mM, from about 30 mM to about 400 mM, fromabout 30 mM to about 350 mM, from about 30 mM to about 300 mM, fromabout 30 mM to about 250 mM, from about 30 mM to about 200 mM, fromabout 30 mM to about 150 mM, from about 30 mM to about 100 mM, fromabout 30 mM to about 75 mM, from about 30 mM to about 50 mM, from about30 mM to about 40 mM, from about 40 mM to about 450 mM, from about 40 mMto about 400 mM, from about 40 mM to about 350 mM, from about 40 mM toabout 300 mM, from about 40 mM to about 250 mM, from about 40 mM toabout 200 mM, from about 40 mM to about 150 mM, from about 40 mM toabout 100 mM, from about 40 mM to about 75 mM, from about 40 mM to about50 mM, from about 50 mM to about 450 mM, from about 50 mM to about 400mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM,from about 50 mM to about 250 mM, from about 50 mM to about 200 mM, fromabout 50 mM to about 150 mM, from about 50 mM to about 100 mM, fromabout 50 mM to about 75 mM, from about 75 mM to about 450 mM, from about75 mM to about 400 mM, from about 75 mM to about 350 mM, from about 75mM to about 300 mM, from about 75 mM to about 250 mM, from about 75 mMto about 200 mM, from about 75 mM to about 150 mM, from about 75 mM toabout 100 mM, from about 100 mM to about 450 mM, from about 100 mM toabout 400 mM, from about 100 mM to about 350 mM, from about 100 mM toabout 300 mM, from about 100 mM to about 250 mM, from about 100 mM toabout 200 mM, from about 100 mM to about 150 mM, from about 150 mM toabout 450 mM, from about 150 mM to about 400 mM, from about 150 mM toabout 350 mM, from about 150 mM to about 300 mM, from about 150 mM toabout 250 mM, from about 150 mM to about 200 mM, from about 200 mM toabout 450 mM, from about 200 mM to about 400 mM, from about 200 mM toabout 350 mM, from about 200 mM to about 300 mM, from about 200 mM toabout 250 mM, from about 250 mM to about 450 mM, from about 250 mM toabout 400 mM, from about 250 mM to about 350 mM, from about 250 mM toabout 300 mM, from about 300 mM to about 450 mM, from about 300 mM toabout 400 mM, from about 300 mM to about 350 mM, from about 350 mM toabout 450 mM, from about 350 mM to about 400 mM, or from about 400 mM toabout 450 mM. In certain embodiments, the concentration of thepharmaceutically acceptable buffer in the liquid pharmaceuticalformulation is from about 25 mM to about 250 mM. In certain embodiments,the concentration of the pharmaceutically acceptable buffer in theliquid pharmaceutical formulation is from about 25 mM to about 100 mM.

In various embodiments, the pharmaceutically acceptable buffer comprisesa buffering agent selected from the group consisting of histidine, acitrate salt, sodium phosphate, potassium phosphate, tromethamine or apharmaceutically acceptable salt thereof, and any combination thereof.

In certain embodiments, the buffering agent is tromethamine or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutically acceptable salt of tromethamine is tromethaminehydrochloride.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;    -   (iii) from about 0.1% (w/w) to about 10% (w/w)        N-methyl-pyrrolidone (NMP);    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 1% (w/w) to about 25% (w/w) N-methyl-pyrrolidone        (NMP);    -   (iii) from about 0.5% (w/w) to about 5% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the liquid pharmaceuticalformulations described herein can be from about 25 mM to about 250 mM,from about 50 mM to about 250 mM, from about 75 mM to about 250 mM, fromabout 100 mM to about 250 mM, from about 125 mM to about 250 mM, fromabout 150 mM to about 250 mM, from about 175 mM to about 250 mM, fromabout 200 mM to about 250 mM, from about 225 mM to about 250 mM, fromabout 25 mM to about 225 mM, from about 25 mM to about 200 mM, fromabout 25 mM to about 175 mM, from about 25 mM to about 150 mM, fromabout 25 mM to about 125 mM, from about 25 mM to about 100 mM, fromabout 25 mM to about 75 mM, from about 25 mM to about 50 mM, from about50 mM to about 225 mM, from about 50 mM to about 200 mM, from about 50mM to about 175 mM, from about 50 mM to about 150 mM, from about 50 mMto about 125 mM, from about 50 mM to about 100 mM, from about 50 mM toabout 75 mM, from about 75 mM to about 225 mM, from about 75 mM to about200 mM, from about 75 mM to about 175 mM, from about 75 mM to about 150mM, from about 75 mM to about 125 mM, from about 75 mM to about 100 mM,from about 100 mM to about 225 mM, from about 100 mM to about 200 mM,from about 100 mM to about 175 mM, from about 100 mM to about 150 mM,from about 100 mM to about 125 mM, from about 125 mM to about 225 mM,from about 125 mM to about 200 mM, from about 125 mM to about 175 mM,from about 125 mM to about 150 mM, from about 150 mM to about 225 mM,from about 150 mM to about 200 mM, from about 150 mM to about 175 mM,from about 150 mM to about 250 mM, from about 175 mM to about 225 mM,from about 175 mM to about 200 mM, or from about 200 mM to about 225 mM.In certain embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the liquid pharmaceuticalformulation is from about 25 mM to about 250 mM. In certain embodiments,the concentration of tromethamine or a pharmaceutically acceptable saltthereof in the liquid pharmaceutical formulation is from about 25 mM toabout 100 mM.

In various embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the liquid pharmaceuticalformulations described herein can be about 25 mM, about 50 mM, about 75mM, about 100 mM, about 125 mM, about 150 mM, about 175 mM, about 200mM, about 225 mM, or about 250 mM. In certain embodiments, theconcentration of tromethamine or a pharmaceutically acceptable saltthereof in the liquid pharmaceutical formulation is about 50 mM.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be from about 50 mg/mLto about 250 mg/mL, from about 60 mg/mL to about 250 mg/mL, from about70 mg/mL to about 250 mg/mL, from about 80 mg/mL to about 250 mg/mL,from about 90 mg/mL to about 250 mg/mL, from about 100 mg/mL to about250 mg/mL, from about 120 mg/mL to about 250 mg/mL, from about 140 mg/mLto about 250 mg/mL, from about 160 mg/mL to about 250 mg/mL, from about180 mg/mL to about 250 mg/mL, from about 200 mg/mL to about 250 mg/mL,from about 50 mg/mL to about 200 mg/mL, from about 50 mg/mL to about 180mg/mL, from about 50 mg/mL to about 160 mg/mL, from about 50 mg/mL toabout 140 mg/mL, from about 50 mg/mL to about 120 mg/mL, from about 50mg/mL to about 100 mg/mL, from about 50 mg/mL to about 90 mg/mL, fromabout 50 mg/mL to about 80 mg/mL, from about 50 mg/mL to about 70 mg/mL,from about 50 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 200mg/mL, from about 60 mg/mL to about 180 mg/mL, from about 60 mg/mL toabout 160 mg/mL, from about 60 mg/mL to about 140 mg/mL, from about 60mg/mL to about 120 mg/mL, from about 60 mg/mL to about 100 mg/mL, fromabout 60 mg/mL to about 90 mg/mL, from about 60 mg/mL to about 80 mg/mL,from about 60 mg/mL to about 70 mg/mL, from about 70 mg/mL to about 200mg/mL, from about 70 mg/mL to about 180 mg/mL, from about 70 mg/mL toabout 160 mg/mL, from about 70 mg/mL to about 140 mg/mL, from about 70mg/mL to about 120 mg/mL, from about 70 mg/mL to about 100 mg/mL, fromabout 70 mg/mL to about 90 mg/mL, from about 70 mg/mL to about 80 mg/mL,from about 80 mg/mL to about 200 mg/mL, from about 80 mg/mL to about 180mg/mL, from about 80 mg/mL to about 160 mg/mL, from about 80 mg/mL toabout 140 mg/mL, from about 80 mg/mL to about 120 mg/mL, from about 80mg/mL to about 100 mg/mL, from about 80 mg/mL to about 90 mg/mL, fromabout 90 mg/mL to about 200 mg/mL, from about 90 mg/mL to about 180mg/mL, from about 90 mg/mL to about 160 mg/mL, from about 90 mg/mL toabout 140 mg/mL, from about 90 mg/mL to about 120 mg/mL, from about 90mg/mL to about 100 mg/mL, from about 100 mg/mL to about 200 mg/mL, fromabout 100 mg/mL to about 180 mg/mL, from about 100 mg/mL to about 160mg/mL, from about 100 mg/mL to about 140 mg/mL, from about 100 mg/mL toabout 120 mg/mL, from about 120 mg/mL to about 200 mg/mL, from about 120mg/mL to about 180 mg/mL, from about 120 mg/mL to about 160 mg/mL, fromabout 120 mg/mL to about 140 mg/mL, from about 140 mg/mL to about 200mg/mL, from about 140 mg/mL to about 180 mg/mL, from about 140 mg/mL toabout 160 mg/mL, from about 160 mg/mL to about 200 mg/mL, from about 160mg/mL to about 180 mg/mL, or from about 180 mg/mL to about 200 mg/mL. Incertain embodiments, the concentration of furosemide in the liquidpharmaceutical formulation is from about 50 mg/mL to about 250 mg/mL,from about 60 mg/mL to about 250 mg/mL, from about 70 mg/mL to about 250mg/mL, or from about 80 mg/mL to about 250 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is from about 80 mg/mL to about 250 mg/mL.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be greater than about40 mg/mL, greater than about 50 mg/mL, greater than about 60 mg/mL,greater than about 70 mg/mL, greater than about 80 mg/mL, greater thanabout 90 mg/mL, greater than about 100 mg/mL, greater than about 120mg/mL, greater than about 140 mg/mL, greater than about 160 mg/mL,greater than about 180 mg/mL, greater than about 200 mg/mL, greater thanabout 220 mg/mL, or greater than about 250 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 40 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 50 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 60 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 70 mg/mL. In certainembodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 80 mg/mL.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be about 40 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, about 100 mg/mL, about 120 mg/mL, about 140 mg/mL, about 160mg/mL, about 180 mg/mL, about 200 mg/mL, about 220 mg/mL, or about 250mg/mL. In certain embodiments, the concentration of furosemide in theliquid pharmaceutical formulation is about 100 mg/mL.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) 100 mg/mL of furosemide, or a pharmaceutically acceptable saltthereof;

(ii) about 4% (w/w) benzyl alcohol; and

(iii) about 50 mM tromethamine or a pharmaceutically acceptable saltthereof.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) 100 mg/mL of furosemide, or a pharmaceutically acceptable saltthereof;

(ii) about 4% (w/w) benzyl alcohol;

(iii) about 0.5 (w/w) N-methyl-pyrrolidone; and

(iv) about 50 mM tromethamine or a pharmaceutically acceptable saltthereof.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 30% (w/w) of one or more        pharmaceutically acceptable excipients selected from the group        consisting of ethanol, benzyl alcohol, glycerin,        N-methyl-pyrrolidone (NMP), sodium chloride, a polyethylene        glycol (PEG), propylene glycol, a polysorbate, a        polyvinylpyrrolidone (PVP), a cyclodextrin, and any combination        thereof; and    -   (iii) from about 25 mM to about 500 mM of a pharmaceutically        acceptable buffer selected from the group consisting of        histidine, a citrate salt, sodium phosphate, potassium        phosphate, tromethamine or a pharmaceutically acceptable salt        thereof, and any combination thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL and the pH of the liquid pharmaceutical formulation is        from about 6.5 to about 8.5.

In various embodiments, the pH of the liquid pharmaceutical formulationsdescribed herein can be from about 5.5 to about 8.5, from about 6 toabout 8.5, from about 6.5 to about 8.5, from about 7 to about 8.5, fromabout 7.5 to about 8.5, from about 8 to about 8.5, from about 5.5 toabout 8, from about 5.5 to about 7.5, from about 5.5 to about 7, fromabout 5.5 to about 6.5, from about 5.5 to about 6, from about 6 to about8, from about 6 to about 7.5, from about 6 to about 7, from about 6 toabout 6.5, from about 6.5 to about 8, from about 6.5 to about 7.5, fromabout 6.5 to about 7, from about 7 to about 8, from about 7 to about7.5, or from about 7.5 to about 8. In certain embodiments, the pH of theliquid pharmaceutical formulation is from about 6.5 to about 8.5. Incertain embodiments, the pH of the liquid pharmaceutical formulation isfrom about 7 to about 8. In certain embodiments, the pH of the liquidpharmaceutical formulation is from about 5.5 to about 6.5.

In various embodiments, the pH of the liquid pharmaceutical formulationsdescribed herein can be about 5.5, about 6, about 6.5, about 7, about7.5, about 8, or about 8.5. In certain embodiments, the pH of the liquidpharmaceutical formulation is about 7.4.

In various embodiments, the pH of the liquid pharmaceutical formulationsdescribed herein can be 5.5±0.1, 6±0.1, 6.5±0.1, 7±0.1, 7.5±0.1, 8±0.1,or 8.5±0.1. In certain embodiments, the pH of the liquid pharmaceuticalformulation is about 7.4±0.1.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 5 mg/mL to about 100 mg/mL and the pH of theliquid pharmaceutical formulation is about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) N-methyl-pyrrolidone (NMP); and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 5 mg/mL to about 100 mg/mL and the pH of theliquid pharmaceutical formulation is about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol;

(iii) N-methyl-pyrrolidone (NMP); and

(iv) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 5 mg/mL to about 100 mg/mL and the pH of theliquid pharmaceutical formulation is about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the liquid pharmaceutical formulation is        about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w)        N-methyl-pyrrolidone;    -   (iii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the liquid pharmaceutical formulation is        about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) furosemide, or a pharmaceutically acceptable salt thereof;    -   (ii) from about 1% (w/w) to about 25% (w/w)        N-methyl-pyrrolidone;    -   (iii) from about 0.5% (w/w) to about 5% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the liquid pharmaceutical formulation is        about from about 5.5 to about 6.5.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be from about 5 mg/mLto about 100 mg/mL, from about 10 mg/mL to about 100 mg/mL, from about 5mg/mL to about 50 mg/mL, from about 5 mg/mL to about 40 mg/mL, fromabout 5 mg/mL to about 30 mg/mL, from about 5 mg/mL to about 20 mg/mL,from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 50mg/mL, from about 10 mg/mL to about 40 mg/mL, from about 10 mg/mL toabout 30 mg/mL, from about 10 mg/mL to about 20 mg/mL, from about 20mg/mL to about 100 mg/mL, from about 30 mg/mL to about 100 mg/mL, fromabout 40 mg/mL to about 100 mg/mL, from about 50 mg/mL to about 100mg/mL, from about 20 mg/mL to about 50 mg/mL, from about 20 mg/mL toabout 40 mg/mL, from about 20 mg/mL to about 30 mg/mL, from about 30mg/mL to about 50 mg/mL, from about 30 mg/mL to about 40 mg/mL, or fromabout 40 mg/mL to about 50 mg/mL. In certain embodiments, theconcentration of furosemide in the liquid pharmaceutical formulation isfrom about 20 mg/mL to about 100 mg/mL. In certain embodiments, theconcentration of furosemide in the liquid pharmaceutical formulation isfrom about 5 mg/mL to about 20 mg/mL.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be greater than about 5mg/mL, greater than about 10 mg/mL, greater than about 20 mg/mL, greaterthan about 30 mg/mL, greater than about 40 mg/mL, greater than about 50mg/mL, greater than about 60 mg/mL, greater than about 70 mg/mL, greaterthan about 80 mg/mL, greater than about 90 mg/mL, or greater than about100 mg/mL. In certain embodiments, the concentration of furosemide inthe liquid pharmaceutical formulation is greater than about 5 mg/mL. Incertain embodiments, the concentration of furosemide in the liquidpharmaceutical formulation is greater than about 20 mg/mL.

In various embodiments, the concentration of furosemide in the liquidpharmaceutical formulations described herein can be about 5 mg/mL, about10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL, about 50mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL,or about 100 mg/mL.

In various embodiments, the liquid pharmaceutical formulations describedherein further comprise a pharmaceutically acceptable pH adjuster. Incertain embodiments, the pharmaceutically acceptable pH adjuster isselected from the group comprising acetic acid, citric acid, fumaricacid, hydrochloric acid, malic acid, nitric acid, phosphoric acid,propionic acid, sulfuric acid, tartaric acid, ammonia solution, ammoniumcarbonate, diethanolamine, potassium hydroxide, sodium bicarbonate,sodium borate, sodium carbonate, sodium hydroxide, trolamine or anycombination thereof. In certain embodiments, the pharmaceuticallyacceptable pH adjuster is sodium hydroxide or hydrochloric acid.

In various embodiments, the liquid pharmaceutical formulations describedherein further comprise an osmolarity adjuster. In some embodiments, theosmolarity adjuster is selected from the group comprising sodiumchloride, potassium chloride, isosorbide, mannitol, xylitol or anycombination thereof. In certain embodiments, the osmolarity adjuster issodium chloride.

In various embodiments, the liquid pharmaceutical formulations describedherein may further comprise one or more additional pharmaceuticallyacceptable carriers, excipients, or diluents. Examples of liquidcarriers for parenteral administration include water, alcohols(including monohydric alcohols and polyhydric alcohols, e.g., glycols)and their derivatives, and oils (e.g., fractionated coconut oil andarachis oil). In some embodiments, the carrier is an oily ester such asethyl oleate and isopropyl myristate. Examples of such carriers are wellknown to those skilled in the art and can be prepared in accordance withacceptable pharmaceutical procedures, such as, for example, thosedescribed in Remington: The Science and Practice of Pharmacy, 20thedition, ed. Alfonso R. Gennaro (Lippincott Williams & Wilkins,Baltimore, Md. (2000)). For example, liquid media or liquid carriers(which are used interchangeably herein) can be used in preparing theliquid pharmaceutical formulations described herein such as solutions,suspensions, and emulsions. In certain embodiments, the pharmaceuticallyacceptable carrier is a sterile carrier.

In certain embodiments, the liquid pharmaceutical formulation comprisesone of more of water; a pH adjuster; and an osmolarity adjuster. Inparticular embodiments, the pH adjuster is selected from the groupconsisting of potassium hydroxide, sodium hydroxide, hydrochloric acid,and combinations thereof. In some embodiments, the osmolarity adjusteris selected from the group consisting of sodium chloride, potassiumchloride, and combinations thereof.

In various embodiments, the liquid pharmaceutical formulations describedherein may further comprise other suitable pharmaceutically acceptableadditives such as solubilizers, emulsifiers, buffers, preservatives,sweeteners, flavoring agents, suspending agents, thickening agents,colors, viscosity regulators, stabilizers, and osmo-regulators.

In various embodiments, the liquid pharmaceutical formulations describedherein further comprise a second therapeutic agent. In certainembodiments, furosemide is the sole therapeutic agent present in theliquid pharmaceutical formulations described herein.

In various embodiments, the liquid pharmaceutical formulations describedherein have an osmolarity in the range of from about 100 mOsm/kg toabout 1600 mOsm/kg, from about 200 mOsm/kg to about 1600 mOsm/kg, fromabout 400 mOsm/kg to about 1600 mOsm/kg, from about 800 mOsm/kg to about1600 mOsm/kg, from about 1200 mOsm/kg to about 1600 mOsm/kg, from about100 mOsm/kg to about 1200 mOsm/kg, from about 100 mOsm/kg to about 800mOsm/kg, from about 100 mOsm/kg to about 400 mOsm/kg, from about 100mOsm/kg to about 200 mOsm/kg, from about 200 mOsm/kg to about 1200mOsm/kg, from about 200 mOsm/kg to about 800 mOsm/kg, from about 200mOsm/kg to about 400 mOsm/kg, from about 400 mOsm/kg to about 1200mOsm/kg, from about 400 mOsm/kg to about 800 mOsm/kg, or from about 800mOsm/kg to about 1200 mOsm/kg. In some embodiments, the liquidpharmaceutical formulations described herein have an osmolarity in therange of from about 200 mOsm/kg to about 400 mOsm/kg.

In certain embodiments, the liquid pharmaceutical formulations describedherein have an osmolarity in the range of from about 275 mOsm/kg toabout 350 mOsm/kg. In certain embodiments, the liquid pharmaceuticalformulations described herein are isosmotic.

Unit Liquid Pharmaceutical Formulations of Furosemide

As described herein, in one aspect, the invention provides unit liquidpharmaceutical formulations of furosemide or a pharmaceuticallyacceptable salt thereof.

In various embodiments, a unit liquid pharmaceutical formulationgenerally comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) one or more pharmaceutically acceptable excipients; and

(iii) a pharmaceutically acceptable buffer.

In various embodiments, the one or more pharmaceutically acceptableexcipients is selected from the group consisting of ethanol, benzylalcohol, glycerin, N-methyl-pyrrolidone (NMP), sodium chloride, apolyethylene glycol (PEG), propylene glycol, a polysorbate, apolyvinylpyrrolidone (PVP), a cyclodextrin, and any combination thereof.In certain embodiments, the PEG has a weight average molecular weight offrom about 3000 g/mol to about 3700 g/mol. In certain embodiments, thepolysorbate is polysorbate 80. In certain embodiments, the PVP has aweight average molecular weight of about 4000 g/mol to about 6000 g/mol.In certain embodiments, the cyclodextrin is β-cyclodextrin.

In certain embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the unit liquid pharmaceutical formulationsdescribed herein can be from about 0.1% (w/w) to about 30% (w/w), fromabout 0.5% (w/w) to about 30% (w/w), from about 1% (w/w) to about 30%(w/w), from about 1.5% (w/w) to about 30% (w/w), (w/w), from about 2%(w/w) to about 30% (w/w), from about 2.5% (w/w) to about 30% (w/w), fromabout 3% (w/w) to about 30% (w/w), from about 3.5% (w/w) to about 30%(w/w), from about 4% (w/w) to about 30% (w/w), from about 4.5% (w/w) toabout 30% (w/w), from about 5% (w/w) to about 30% (w/w), from about 10%(w/w) to about 30% (w/w), from about 15% (w/w) to about 30% (w/w), fromabout 20% (w/w) to about 30% (w/w), from about 25% (w/w) to about 30%(w/w), from about 0.1% (w/w) to about 25% (w/w), from about 0.1% (w/w)to about 20% (w/w), from about 0.1% (w/w) to about 15% (w/w), from about0.1% (w/w) to about 10% (w/w), from about 0.1% (w/w) to about 5% (w/w),from about 0.1% (w/w) to about 4.5% (w/w), from about 0.1% (w/w) toabout 4% (w/w), from about 0.1% (w/w) to about 3.5% (w/w), from about0.1% (w/w) to about 3% (w/w), from about 0.1% (w/w) to about 2.5% (w/w),from about 0.1% (w/w) to about 2% (w/w), from about 0.1% (w/w) to about1.5% (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1%(w/w) to about 0.5% (w/w), from about 0.5% (w/w) to about 25% (w/w),from about 0.5% (w/w) to about 20% (w/w), from about 0.5% (w/w) to about15% (w/w), from about 0.5% (w/w) to about 10% (w/w), from about 0.5%(w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4.5% (w/w), fromabout 0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3.5%(w/w), from about 0.5% (w/w) to about 3% (w/w), from about 0.5% (w/w) toabout 2.5% (w/w), from about 0.5% (w/w) to about 2% (w/w), from about0.5% (w/w) to about 1.5% (w/w), from about 0.5% (w/w) to about 1% (w/w),from about 1% (w/w) to about 25% (w/w), from about 1% (w/w) to about 20%(w/w), from about 1% (w/w) to about 15% (w/w), from about 1% (w/w) toabout 10% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1%(w/w) to about 4.5% (w/w), from about 1% (w/w) to about 4% (w/w), fromabout 1% (w/w) to about 3.5% (w/w), from about 1% (w/w) to about 2.5%(w/w), from about 1% (w/w) to about 2% (w/w), from about 1% (w/w) toabout 1.5% (w/w), from about 1.5% (w/w) to about 25% (w/w), from about1.5% (w/w) to about 20% (w/w), from about 1.5% (w/w) to about 15% (w/w),from about 1.5% (w/w) to about 10% (w/w), from about 1.5% (w/w) to about5% (w/w), from about 1.5% (w/w) to about 4.5% (w/w), from about 1.5%(w/w) to about 4% (w/w), from about 1.5% (w/w) to about 3.5% (w/w), fromabout 1.5% (w/w) to about 3% (w/w), from about 1.5% (w/w) to about 2.5%(w/w), from about 1.5% (w/w) to about 2% (w/w), from about 2% (w/w) toabout 25% (w/w), from about 2% (w/w) to about 20% (w/w), from about 2%(w/w) to about 15% (w/w), from about 2% (w/w) to about 10% (w/w), fromabout 2% (w/w) to about 5% (w/w), from about 2% (w/w) to about 4.5%(w/w), from about 2% (w/w) to about 4% (w/w), from about 2% (w/w) toabout 3.5% (w/w), from about 2% (w/w) to about 3% (w/w), from about 2%(w/w) to about 2.5% (w/w), from about 2.5% (w/w) to about 25% (w/w),from about 2.5% (w/w) to about 20% (w/w), from about 2.5% (w/w) to about15% (w/w), from about 2.5% (w/w) to about 10% (w/w), from about 2.5%(w/w) to about 5% (w/w), from about 2.5% (w/w) to about 4.5% (w/w), fromabout 2.5% (w/w) to about 4% (w/w), from about 2.5% (w/w) to about 3.5%(w/w), from about 2.5% (w/w) to about 3% (w/w), from about 3% (w/w) toabout 25% (w/w), from about 3% (w/w) to about 20% (w/w), from about 3%(w/w) to about 15% (w/w), from about 3% (w/w) to about 10% (w/w), fromabout 3% (w/w) to about 5% (w/w), from about 3% (w/w) to about 4.5%(w/w), from about 3% (w/w) to about 4% (w/w), from about 3% (w/w) toabout 3.5% (w/w), from about 3.5% (w/w) to about 25% (w/w), from about3.5% (w/w) to about 20% (w/w), from about 3.5% (w/w) to about 15% (w/w),from about 3.5% (w/w) to about 10% (w/w), from about 3.5% (w/w) to about5% (w/w), from about 3.5% (w/w) to about 4.5% (w/w), from about 3.5%(w/w) to about 4% (w/w), from about 4% (w/w) to about 25% (w/w), fromabout 4% (w/w) to about 20% (w/w), from about 4% (w/w) to about 15%(w/w), from about 4% (w/w) to about 10% (w/w), from about 4% (w/w) toabout 5% (w/w), from about 4% (w/w) to about 4.5% (w/w), from about 4.5%(w/w) to about 25% (w/w), from about 4.5% (w/w) to about 20% (w/w), fromabout 4.5% (w/w) to about 15% (w/w), from about 4.5% (w/w) to about 10%(w/w), from about 4.5% (w/w) to about 5% (w/w), from about 5% (w/w) toabout 25% (w/w), from about 5% (w/w) to about 20% (w/w), from about 5%(w/w) to about 15% (w/w), from about 5% (w/w) to about 10% (w/w), fromabout 10% (w/w) to about 25% (w/w), from about 10% (w/w) to about 20%(w/w), from about 10% (w/w) to about 15% (w/w), from about 15% (w/w) toabout 25% (w/w), from about 15% (w/w) to about 20% (w/w), or from about20% (w/w) to about 25% (w/w). In certain embodiments, the amount of theone or more pharmaceutically acceptable excipients in the unit liquidpharmaceutical formulation is from about 1.5% (w/w) to about 30% (w/w).In certain embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the unit liquid pharmaceutical formulation isfrom about 5% (w/w) to about 15% (w/w). In certain embodiments, theamount of the one or more pharmaceutically acceptable excipients in theunit liquid pharmaceutical formulation is from about 0.1% (w/w) to about10% (w/w). In certain embodiments, the amount of the one or morepharmaceutically acceptable excipients in the unit liquid pharmaceuticalformulation is from about 0.5% (w/w) to about 5% (w/w).

In various embodiments, the amount of the one or more pharmaceuticallyacceptable excipients in the unit liquid pharmaceutical formulationsdescribed herein can about 0.1% (w/w), about 0.25% (w/w), about 0.5%(w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5%(w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5%(w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w),about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17%(w/w), about 18% (w/w), about 19% (w/w), about 20% (w/w), about 21%(w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25%(w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29%(w/w), or about 30% (w/w).

In certain embodiments, the one or more pharmaceutically acceptableexcipients comprises benzyl alcohol. In certain embodiments, the one ormore pharmaceutically acceptable excipients comprises NMP. In certainembodiments, the one or more pharmaceutically acceptable excipientscomprises NMP and benzyl alcohol.

In various embodiments, the concentration of the pharmaceuticallyacceptable buffer in the unit liquid pharmaceutical formulationsdescribed herein can be from about 25 mM to about 500 mM, from about 30mM to about 500 mM, from about 40 mM to about 500 mM, from about 50 mMto about 500 mM, from about 75 mM to about 500 mM, from about 100 mM toabout 500 mM, from about 150 mM to about 500 mM, from about 200 mM toabout 500 mM, from about 200 mM to about 500 mM, from about 250 mM toabout 500 mM, from about 300 mM to about 500 mM, from about 350 mM toabout 500 mM, from about 400 mM to about 500 mM, from about 450 mM toabout 500 mM, from about 25 mM to about 450 mM, from about 25 mM toabout 400 mM, from about 25 mM to about 350 mM, from about 25 mM toabout 300 mM, from about 25 mM to about 250 mM, from about 25 mM toabout 200 mM, from about 25 mM to about 150 mM, from about 25 mM toabout 100 mM, from about 25 mM to about 75 mM, from about 25 mM to about50 mM, from about 25 mM to about 40 mM, from about 25 mM to about 30 mM,from about 30 mM to about 450 mM, from about 30 mM to about 400 mM, fromabout 30 mM to about 350 mM, from about 30 mM to about 300 mM, fromabout 30 mM to about 250 mM, from about 30 mM to about 200 mM, fromabout 30 mM to about 150 mM, from about 30 mM to about 100 mM, fromabout 30 mM to about 75 mM, from about 30 mM to about 50 mM, from about30 mM to about 40 mM, from about 40 mM to about 450 mM, from about 40 mMto about 400 mM, from about 40 mM to about 350 mM, from about 40 mM toabout 300 mM, from about 40 mM to about 250 mM, from about 40 mM toabout 200 mM, from about 40 mM to about 150 mM, from about 40 mM toabout 100 mM, from about 40 mM to about 75 mM, from about 40 mM to about50 mM, from about 50 mM to about 450 mM, from about 50 mM to about 400mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM,from about 50 mM to about 250 mM, from about 50 mM to about 200 mM, fromabout 50 mM to about 150 mM, from about 50 mM to about 100 mM, fromabout 50 mM to about 75 mM, from about 75 mM to about 450 mM, from about75 mM to about 400 mM, from about 75 mM to about 350 mM, from about 75mM to about 300 mM, from about 75 mM to about 250 mM, from about 75 mMto about 200 mM, from about 75 mM to about 150 mM, from about 75 mM toabout 100 mM, from about 100 mM to about 450 mM, from about 100 mM toabout 400 mM, from about 100 mM to about 350 mM, from about 100 mM toabout 300 mM, from about 100 mM to about 250 mM, from about 100 mM toabout 200 mM, from about 100 mM to about 150 mM, from about 150 mM toabout 450 mM, from about 150 mM to about 400 mM, from about 150 mM toabout 350 mM, from about 150 mM to about 300 mM, from about 150 mM toabout 250 mM, from about 150 mM to about 200 mM, from about 200 mM toabout 450 mM, from about 200 mM to about 400 mM, from about 200 mM toabout 350 mM, from about 200 mM to about 300 mM, from about 200 mM toabout 250 mM, from about 250 mM to about 450 mM, from about 250 mM toabout 400 mM, from about 250 mM to about 350 mM, from about 250 mM toabout 300 mM, from about 300 mM to about 450 mM, from about 300 mM toabout 400 mM, from about 300 mM to about 350 mM, from about 350 mM toabout 450 mM, from about 350 mM to about 400 mM, or from about 400 mM toabout 450 mM. In certain embodiments, the concentration of thepharmaceutically acceptable buffer in the unit liquid pharmaceuticalformulation is from about 25 mM to about 250 mM. In certain embodiments,the concentration of the pharmaceutically acceptable buffer in the unitliquid pharmaceutical formulation is from about 25 mM to about 100 mM.

In various embodiments, the pharmaceutically acceptable buffer comprisesa buffering agent selected from the group consisting of histidine, acitrate salt, sodium phosphate, potassium phosphate, tromethamine or apharmaceutically acceptable salt thereof, and any combination thereof.

In certain embodiments, the buffering agent is tromethamine or apharmaceutically acceptable salt thereof.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) benzyl alcohol; and

(iii) tromethamine or a pharmaceutically acceptable salt thereof.

In certain embodiments, the unit liquid pharmaceutical formulationsfurther comprise N-methyl-pyrrolidone (NMP).

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) N-methyl-pyrrolidone (NMP);

(iii) benzyl alcohol; and

(iv) tromethamine or a pharmaceutically acceptable salt thereof.

In various embodiments, the amount of furosemide, or a pharmaceuticallyacceptable salt thereof, in the unit liquid pharmaceutical formulationsdescribed herein can be from about 20 mg to about 200 mg, from about 40mg to about 200 mg, from about 60 mg to about 200 mg, from about 80 mgto about 200 mg, from about 100 mg to about 200 mg, from about 120 mg toabout 200 mg, from about 140 mg to about 200 mg, from about 160 mg toabout 200 mg, from about 180 mg to about 200 mg, from about 20 mg toabout 180 mg, from about 20 mg to about 160 mg, from about 20 mg toabout 140 mg, from about 20 mg to about 120 mg, from about 20 mg toabout 100 mg, from about 20 mg to about 80 mg, from about 20 mg to about60 mg, from about 20 mg to about 40 mg, from about 40 mg to about 180mg, from about 40 mg to about 160 mg, from about 40 mg to about 140 mg,from about 40 mg to about 120 mg, from about 40 mg to about 100 mg, fromabout 40 mg to about 80 mg, from about 40 mg to about 60 mg, from about60 mg to about 180 mg, from about 60 mg to about 160 mg, from about 60mg to about 140 mg, from about 60 mg to about 120 mg, from about 60 mgto about 100 mg, from about 60 mg to about 80 mg, from about 80 mg toabout 180 mg, from about 80 mg to about 160 mg, from about 80 mg toabout 140 mg, from about 80 mg to about 120 mg, from about 80 mg toabout 100 mg, from about 100 mg to about 180 mg, from about 100 mg toabout 160 mg, from about 100 mg to about 140 mg, from about 100 mg toabout 120 mg, from about 120 mg to about 180 mg, from about 120 mg toabout 160 mg, from about 120 mg to about 140 mg, from about 140 mg toabout 180 mg, from about 140 mg to about 160 mg, or from about 160 mg toabout 180 mg. In certain embodiments, the amount of furosemide, or apharmaceutically acceptable salt thereof, in the unit liquidpharmaceutical formulations is from about 20 mg to about 200 mg, fromabout 40 mg to about 200 mg, from about 60 mg to about 200 mg, or fromabout 80 mg to about 200 mg. In some embodiments, the amount offurosemide, or a pharmaceutically acceptable salt thereof, in the unitliquid pharmaceutical formulation is from about 80 mg to about 200 mg.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein comprise about 10 mg, about 20 mg, about 30 mg, about40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,about 100 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg,about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mgof furosemide, or a pharmaceutically acceptable salt thereof.

In various embodiments, the amount of benzyl alcohol in the unit liquidpharmaceutical formulations described herein can be from about 0.1%(w/w) to about 10% (w/w), from about 0.5% (w/w) to about 10% (w/w), fromabout 1% (w/w) to about 10% (w/w), from about 2% (w/w) to about 10%(w/w), from about 3% (w/w) to about 10% (w/w), from about 4% (w/w) toabout 10% (w/w), from about 5% (w/w) to about 10% (w/w), from about 0.1%(w/w) to about 5% (w/w), from about 0.1% (w/w) to about 4% (w/w), fromabout 0.1% (w/w) to about 3% (w/w), from about 0.1% (w/w) to about 2%(w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1% (w/w) toabout 0.5% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w),from about 0.5% (w/w) to about 2% (w/w), from about 0.5% (w/w) to about1% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1% (w/w) toabout 4% (w/w), from about 1% (w/w) to about 3% (w/w), from about 1%(w/w) to about 2% (w/w), from about 2% (w/w) to about 5% (w/w), fromabout 2% (w/w) to about 4% (w/w), from about 2% (w/w) to about 3% (w/w),from about 3% (w/w) to about 5% (w/w), from about 3% (w/w) to about 4%(w/w), or from about 4% (w/w) to about 5% (w/w). In certain embodiments,the amount of benzyl alcohol in the unit liquid pharmaceuticalformulation is from about 0.1% (w/w) to about 10% (w/w). In certainembodiments, the amount of benzyl alcohol in the unit liquidpharmaceutical formulation is from about 0.5% (w/w) to about 5% (w/w).

In various embodiments, the amount of benzyl alcohol in the unit liquidpharmaceutical formulations described herein can be about 0.1% (w/w),about 0.5% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w),about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w),about 4.5% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about8% (w/w), about 9% (w/w), or about 10% (w/w). In certain embodiments,the amount of benzyl alcohol in the unit liquid pharmaceuticalformulation is about 4% (w/w).

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In certain embodiments, the unit liquid pharmaceutical formulationsfurther comprise N-methyl-pyrrolidone (NMP).

In various embodiments, the amount of NMP in the unit liquidpharmaceutical formulations described herein can be from about 0.1%(w/w) to about 10% (w/w), from about 0.5% (w/w) to about 10% (w/w), fromabout 1% (w/w) to about 10% (w/w), from about 2% (w/w) to about 10%(w/w), from about 3% (w/w) to about 10% (w/w), from about 4% (w/w) toabout 10% (w/w), from about 5% (w/w) to about 10% (w/w), from about 0.1%(w/w) to about 5% (w/w), from about 0.1% (w/w) to about 4% (w/w), fromabout 0.1% (w/w) to about 3% (w/w), from about 0.1% (w/w) to about 2%(w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1% (w/w) toabout 0.5% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about0.5% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w),from about 0.5% (w/w) to about 2% (w/w), from about 0.5% (w/w) to about1% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1% (w/w) toabout 4% (w/w), from about 1% (w/w) to about 3% (w/w), from about 1%(w/w) to about 2% (w/w), from about 2% (w/w) to about 5% (w/w), fromabout 2% (w/w) to about 4% (w/w), from about 2% (w/w) to about 3% (w/w),from about 3% (w/w) to about 5% (w/w), from about 3% (w/w) to about 4%(w/w), or from about 4% (w/w) to about 5% (w/w). In certain embodiments,the amount of NMP in the unit liquid pharmaceutical formulation is fromabout 0.1% (w/w) to about 10% (w/w). In certain embodiments, the amountof NMP in the unit liquid pharmaceutical formulation is from about 0.1%(w/w) to about 1% (w/w).

In various embodiments, the amount of NMP in the unit liquidpharmaceutical formulations described herein can be about 0.1% (w/w),about 0.5% (w/w), about 1% (w/w), about 1.5% (w/w), about 2% (w/w),about 2.5% (w/w), about 3% (w/w), about 3.5% (w/w), about 4% (w/w),about 4.5% (w/w), about 5% (w/w), about 5.5% (w/w), about 6% (w/w),about 6.5% (w/w), about 7% (w/w), about 7.5% (w/w), about 8% (w/w),about 8.5% (w/w), about 9% (w/w), about 9.5% (w/w), or about 10% (w/w).In some embodiments, the amount of NMP in the unit liquid pharmaceuticalformulation is about 0.5 (w/w).

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;    -   (iii) from about 0.1% (w/w) to about 10% (w/w)        N-methyl-pyrrolidone (NMP); and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) N-methyl-pyrrolidone (NMP); and    -   (iii) a pharmaceutically acceptable buffer,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, the amount of NMP in the unit liquidpharmaceutical formulations described herein can be from about 1% (w/w)to about 25% (w/w), from about 2.5% (w/w) to about 25% (w/w), from about5% (w/w) to about 25% (w/w), from about 7.5% (w/w) to about 25% (w/w),from about 10% (w/w) to about 25% (w/w), from about 12.5% (w/w) to about25% (w/w), from about 15% (w/w) to about 25% (w/w), from about 20% (w/w)to about 25% (w/w), from about 1% (w/w) to about 20% (w/w), from about1% (w/w) to about 15% (w/w), from about 1% (w/w) to about 12.5% (w/w),from about 1% (w/w) to about 10% (w/w), from about 1% (w/w) to about7.5% (w/w), from about 1% (w/w) to about 5% (w/w), from about 1% (w/w)to about 2.5% (w/w), from about 2.5% (w/w) to about 20% (w/w), fromabout 2.5% (w/w) to about 15% (w/w), from about 2.5% (w/w) to about12.5% (w/w), from about 2.5% (w/w) to about 10% (w/w), from about 2.5%(w/w) to about 7.5% (w/w), from about 2.5% (w/w) to about 5% (w/w), fromabout 5% (w/w) to about 20% (w/w), from about 5% (w/w) to about 15%(w/w), from about 5% (w/w) to about 12.5% (w/w), from about 5% (w/w) toabout 10% (w/w), from about 5% (w/w) to about 7.5% (w/w), from about7.5% (w/w) to about 20% (w/w), from about 7.5% (w/w) to about 15% (w/w),from about 7.5% (w/w) to about 12.5% (w/w), from about 7.5% (w/w) toabout 10% (w/w), from about 10% (w/w) to about 20% (w/w), from about 10%(w/w) to about 15% (w/w), from about 10% (w/w) to about 12.5% (w/w),from about 12.5% (w/w) to about 20% (w/w), from about 12.5% (w/w) toabout 15% (w/w), from about 12.5% (w/w) to about 20% (w/w), from about12.5% (w/w) to about 15% (w/w), or from about 15% (w/w) to about 20%(w/w). In certain embodiments, the amount of NMP in the unit liquidpharmaceutical formulation is from about 1% (w/w) to about 25% (w/w). Incertain embodiments, the amount of NMP in the unit liquid pharmaceuticalformulation is from about 5% (w/w) to about 10% (w/w).

In various embodiments, the amount of NMP in the unit liquidpharmaceutical formulations described herein can be about 1% (w/w),about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w), about 3% (w/w),about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), about 5% (w/w),about 5.5% (w/w), about 6% (w/w), about 6.5% (w/w), about 7% (w/w),about 7.5% (w/w), about 8% (w/w), about 8.5% (w/w), about 9% (w/w),about 9.5% (w/w), about 10% (w/w), about 12.5% (w/w), about 15% (w/w),about 20% (w/w), or about 25% (w/w).

In certain embodiments, the unit liquid pharmaceutical formulationfurther comprises benzyl alcohol.

In various embodiments, the amount of benzyl alcohol in the unit liquidpharmaceutical formulations described herein can be from about 0.5%(w/w) to about 5% (w/w), from about 1% (w/w) to about 5% (w/w), fromabout 2% (w/w) to about 5% (w/w), from about 3% (w/w) to about 5% (w/w),from about 4% (w/w) to about 5% (w/w), from about 0.5% (w/w) to about 4%(w/w), from about 0.5% (w/w) to about 3% (w/w), from about 0.5% (w/w) toabout 2% (w/w), from about 0.5% (w/w) to about 1% (w/w), from about 1%(w/w) to about 4% (w/w), from about 1% (w/w) to about 3% (w/w), fromabout 1% (w/w) to about 2% (w/w), from about 2% (w/w) to about 4% (w/w),from about 2% (w/w) to about 3% (w/w), or from about 3% (w/w) to about4% (w/w). In certain embodiments, the amount of benzyl alcohol in theunit liquid pharmaceutical formulation is from about 0.5% (w/w) to about5% (w/w). In certain embodiments, the amount of benzyl alcohol in theunit liquid pharmaceutical formulation is from about 1% (w/w) to about3% (w/w).

In various embodiments, the amount of benzyl alcohol in the unit liquidpharmaceutical formulations described herein can be about 0.5% (w/w),about 1% (w/w), about 1.5% (w/w), about 2% (w/w), about 2.5% (w/w),about 3% (w/w), about 3.5% (w/w), about 4% (w/w), about 4.5% (w/w), orabout 5% (w/w).

In some embodiments, the pharmaceutically acceptable salt oftromethamine is tromethamine hydrochloride.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 30% (w/w) of one or more        pharmaceutically acceptable excipients selected from the group        consisting of ethanol, benzyl alcohol, glycerin,        N-methyl-pyrrolidone (NMP), sodium chloride, a polyethylene        glycol (PEG), propylene glycol, a polysorbate, a        polyvinylpyrrolidone (PVP), a cyclodextrin, and any combination        thereof; and    -   (iii) from about 25 mM to about 500 mM of a pharmaceutically        acceptable buffer selected from the group consisting of        histidine, a citrate salt, sodium phosphate, potassium        phosphate, tromethamine or a pharmaceutically acceptable salt        thereof, and any combination thereof,        wherein the concentration of furosemide in the liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL and the pH of the liquid pharmaceutical formulation is        from about 6.5 to about 8.5.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;    -   (iii) from about 0.1% (w/w) to about 10% (w/w)        N-methyl-pyrrolidone (NMP);    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 1% (w/w) to about 25% (w/w) N-methyl-pyrrolidone        (NMP);    -   (iii) from about 0.5% (w/w) to about 5% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 40 mg/mL to about 250        mg/mL.

In various embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the unit liquidpharmaceutical formulations described herein can be from about 25 mM toabout 250 mM, from about 50 mM to about 250 mM, from about 75 mM toabout 250 mM, from about 100 mM to about 250 mM, from about 125 mM toabout 250 mM, from about 150 mM to about 250 mM, from about 175 mM toabout 250 mM, from about 200 mM to about 250 mM, from about 225 mM toabout 250 mM, from about 25 mM to about 225 mM, from about 25 mM toabout 200 mM, from about 25 mM to about 175 mM, from about 25 mM toabout 150 mM, from about 25 mM to about 125 mM, from about 25 mM toabout 100 mM, from about 25 mM to about 75 mM, from about 25 mM to about50 mM, from about 50 mM to about 225 mM, from about 50 mM to about 200mM, from about 50 mM to about 175 mM, from about 50 mM to about 150 mM,from about 50 mM to about 125 mM, from about 50 mM to about 100 mM, fromabout 50 mM to about 75 mM, from about 75 mM to about 225 mM, from about75 mM to about 200 mM, from about 75 mM to about 175 mM, from about 75mM to about 150 mM, from about 75 mM to about 125 mM, from about 75 mMto about 100 mM, from about 100 mM to about 225 mM, from about 100 mM toabout 200 mM, from about 100 mM to about 175 mM, from about 100 mM toabout 150 mM, from about 100 mM to about 125 mM, from about 125 mM toabout 225 mM, from about 125 mM to about 200 mM, from about 125 mM toabout 175 mM, from about 125 mM to about 150 mM, from about 150 mM toabout 225 mM, from about 150 mM to about 200 mM, from about 150 mM toabout 175 mM, from about 150 mM to about 250 mM, from about 175 mM toabout 225 mM, from about 175 mM to about 200 mM, or from about 200 mM toabout 225 mM. In certain embodiments, the concentration of tromethamineor a pharmaceutically acceptable salt thereof in the unit liquidpharmaceutical formulation is from about 25 mM to about 250 mM. Incertain embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the unit liquidpharmaceutical formulation is from about 25 mM to about 100 mM.

In various embodiments, the concentration of tromethamine or apharmaceutically acceptable salt thereof in the unit liquidpharmaceutical formulations described herein can be about 25 mM, about50 mM, about 75 mM, about 100 mM, about 125 mM, about 150 mM, about 175mM, about 200 mM, about 225 mM, or about 250 mM. In certain embodiments,the concentration of tromethamine or a pharmaceutically acceptable saltthereof in the unit liquid pharmaceutical formulation is about 50 mM.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be from about 50mg/mL to about 250 mg/mL, from about 60 mg/mL to about 250 mg/mL, fromabout 70 mg/mL to about 250 mg/mL, from about 80 mg/mL to about 250mg/mL, from about 90 mg/mL to about 250 mg/mL, from about 100 mg/mL toabout 250 mg/mL, from about 120 mg/mL to about 250 mg/mL, from about 140mg/mL to about 250 mg/mL, from about 160 mg/mL to about 250 mg/mL, fromabout 180 mg/mL to about 250 mg/mL, from about 200 mg/mL to about 250mg/mL, from about 50 mg/mL to about 200 mg/mL, from about 50 mg/mL toabout 180 mg/mL, from about 50 mg/mL to about 160 mg/mL, from about 50mg/mL to about 140 mg/mL, from about 50 mg/mL to about 120 mg/mL, fromabout 50 mg/mL to about 100 mg/mL, from about 50 mg/mL to about 90mg/mL, from about 50 mg/mL to about 80 mg/mL, from about 50 mg/mL toabout 70 mg/mL, from about 50 mg/mL to about 60 mg/mL, from about 60mg/mL to about 200 mg/mL, from about 60 mg/mL to about 180 mg/mL, fromabout 60 mg/mL to about 160 mg/mL, from about 60 mg/mL to about 140mg/mL, from about 60 mg/mL to about 120 mg/mL, from about 60 mg/mL toabout 100 mg/mL, from about 60 mg/mL to about 90 mg/mL, from about 60mg/mL to about 80 mg/mL, from about 60 mg/mL to about 70 mg/mL, fromabout 70 mg/mL to about 200 mg/mL, from about 70 mg/mL to about 180mg/mL, from about 70 mg/mL to about 160 mg/mL, from about 70 mg/mL toabout 140 mg/mL, from about 70 mg/mL to about 120 mg/mL, from about 70mg/mL to about 100 mg/mL, from about 70 mg/mL to about 90 mg/mL, fromabout 70 mg/mL to about 80 mg/mL, from about 80 mg/mL to about 200mg/mL, from about 80 mg/mL to about 180 mg/mL, from about 80 mg/mL toabout 160 mg/mL, from about 80 mg/mL to about 140 mg/mL, from about 80mg/mL to about 120 mg/mL, from about 80 mg/mL to about 100 mg/mL, fromabout 80 mg/mL to about 90 mg/mL, from about 90 mg/mL to about 200mg/mL, from about 90 mg/mL to about 180 mg/mL, from about 90 mg/mL toabout 160 mg/mL, from about 90 mg/mL to about 140 mg/mL, from about 90mg/mL to about 120 mg/mL, from about 90 mg/mL to about 100 mg/mL, fromabout 100 mg/mL to about 200 mg/mL, from about 100 mg/mL to about 180mg/mL, from about 100 mg/mL to about 160 mg/mL, from about 100 mg/mL toabout 140 mg/mL, from about 100 mg/mL to about 120 mg/mL, from about 120mg/mL to about 200 mg/mL, from about 120 mg/mL to about 180 mg/mL, fromabout 120 mg/mL to about 160 mg/mL, from about 120 mg/mL to about 140mg/mL, from about 140 mg/mL to about 200 mg/mL, from about 140 mg/mL toabout 180 mg/mL, from about 140 mg/mL to about 160 mg/mL, from about 160mg/mL to about 200 mg/mL, from about 160 mg/mL to about 180 mg/mL, orfrom about 180 mg/mL to about 200 mg/mL. In certain embodiments, theconcentration of furosemide in the unit liquid pharmaceuticalformulation is from about 50 mg/mL to about 250 mg/mL, from about 60mg/mL to about 250 mg/mL, from about 70 mg/mL to about 250 mg/mL, orfrom about 80 mg/mL to about 250 mg/mL. In certain embodiments, theconcentration of furosemide in the unit liquid pharmaceuticalformulation is from about 80 mg/mL to about 250 mg/mL.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be greater thanabout 40 mg/mL, greater than about 50 mg/mL, greater than about 60mg/mL, greater than about 70 mg/mL, greater than about 80 mg/mL, greaterthan about 90 mg/mL, greater than about 100 mg/mL, greater than about120 mg/mL, greater than about 140 mg/mL, greater than about 160 mg/mL,greater than about 180 mg/mL, greater than about 200 mg/mL, greater thanabout 220 mg/mL, or greater than about 250 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is greater than about 40 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is greater than about 50 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is greater than about 60 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is greater than about 70 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is greater than about 80 mg/mL.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be about 40mg/mL, about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL,about 90 mg/mL, about 100 mg/mL, about 120 mg/mL, about 140 mg/mL, about160 mg/mL, about 180 mg/mL, about 200 mg/mL, about 220 mg/mL, or about250 mg/mL. In certain embodiments, the concentration of furosemide inthe unit liquid pharmaceutical formulation is about 100 mg/mL.

In various embodiments, the pH of the unit liquid pharmaceuticalformulations described herein can be from about 5.5 to about 8.5, fromabout 6 to about 8.5, from about 6.5 to about 8.5, from about 7 to about8.5, from about 7.5 to about 8.5, from about 8 to about 8.5, from about5.5 to about 8, from about 5.5 to about 7.5, from about 5.5 to about 7,from about 5.5 to about 6.5, from about 5.5 to about 6, from about 6 toabout 8, from about 6 to about 7.5, from about 6 to about 7, from about6 to about 6.5, from about 6.5 to about 8, from about 6.5 to about 7.5,from about 6.5 to about 7, from about 7 to about 8, from about 7 toabout 7.5, or from about 7.5 to about 8. In certain embodiments, the pHof the unit liquid pharmaceutical formulation is from about 6.5 to about8.5. In certain embodiments, the pH of the unit liquid pharmaceuticalformulation is from about 7 to about 8. In certain embodiments, the pHof the unit liquid pharmaceutical formulation is from about 5.5 to about6.5.

In various embodiments, the pH of the unit liquid pharmaceuticalformulations described herein can be about 5.5, about 6, about 6.5,about 7, about 7.5, about 8, or about 8.5. In certain embodiments, thepH of the unit liquid pharmaceutical formulation is about 7.4.

In various embodiments, the pH of the unit liquid pharmaceuticalformulations described herein can be 5.5±0.1, 6±0.1, 6.5±0.1, 7±0.1,7.5±0.1, 8±0.1, or 8.5±0.1. In certain embodiments, the pH of the unitliquid pharmaceutical formulation is about 7.4±0.1.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iii) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the unit liquid pharmaceutical formulation        is about from about 5.5 to about 6.5.

In various embodiments, a unit liquid pharmaceutical formulationcomprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 0.1% (w/w) to about 10% (w/w)        N-methyl-pyrrolidone;    -   (iii) from about 0.1% (w/w) to about 10% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the unit liquid pharmaceutical formulation        is about from about 5.5 to about 6.5.

In various embodiments, a liquid pharmaceutical formulation comprises:

-   -   (i) from about 10 mg to about 200 mg furosemide, or a        pharmaceutically acceptable salt thereof;    -   (ii) from about 1% (w/w) to about 25% (w/w)        N-methyl-pyrrolidone;    -   (iii) from about 0.5% (w/w) to about 5% (w/w) benzyl alcohol;        and    -   (iv) from about 25 mM to about 250 mM tromethamine or a        pharmaceutically acceptable salt thereof,        wherein the concentration of furosemide in the unit liquid        pharmaceutical formulation is from about 5 mg/mL to about 100        mg/mL and the pH of the unit liquid pharmaceutical formulation        is about from about 5.5 to about 6.5.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be from about 5mg/mL to about 100 mg/mL, from about 10 mg/mL to about 100 mg/mL, fromabout 5 mg/mL to about 50 mg/mL, from about 5 mg/mL to about 40 mg/mL,from about 5 mg/mL to about 30 mg/mL, from about 5 mg/mL to about 20mg/mL, from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL toabout 50 mg/mL, from about 10 mg/mL to about 40 mg/mL, from about 10mg/mL to about 30 mg/mL, from about 10 mg/mL to about 20 mg/mL, fromabout 20 mg/mL to about 100 mg/mL, from about 30 mg/mL to about 100mg/mL, from about 40 mg/mL to about 100 mg/mL, from about 50 mg/mL toabout 100 mg/mL, from about 20 mg/mL to about 50 mg/mL, from about 20mg/mL to about 40 mg/mL, from about 20 mg/mL to about 30 mg/mL, fromabout 30 mg/mL to about 50 mg/mL, from about 30 mg/mL to about 40 mg/mL,or from about 40 mg/mL to about 50 mg/mL. In certain embodiments, theconcentration of furosemide in the unit liquid pharmaceuticalformulation is from about 20 mg/mL to about 100 mg/mL. In certainembodiments, the concentration of furosemide in the unit liquidpharmaceutical formulation is from about 5 mg/mL to about 20 mg/mL.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be greater thanabout 5 mg/mL, greater than about 10 mg/mL, greater than about 20 mg/mL,greater than about 30 mg/mL, greater than about 40 mg/mL, greater thanabout 50 mg/mL, greater than about 60 mg/mL, greater than about 70mg/mL, greater than about 80 mg/mL, greater than about 90 mg/mL, orgreater than about 100 mg/mL. In certain embodiments, the concentrationof furosemide in the unit liquid pharmaceutical formulation is greaterthan about 5 mg/mL. In certain embodiments, the concentration offurosemide in the unit liquid pharmaceutical formulation is greater thanabout 20 mg/mL.

In various embodiments, the concentration of furosemide in the unitliquid pharmaceutical formulations described herein can be about 5mg/mL, about 10 mg/mL, about 20 mg/mL, about 30 mg/mL, about 40 mg/mL,about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90mg/mL, or about 100 mg/mL.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein further comprise a pharmaceutically acceptable pHadjuster. In certain embodiments, the pharmaceutically acceptable pHadjuster is selected from the group consisting of acetic acid, citricacid, fumaric acid, hydrochloric acid, malic acid, nitric acid,phosphoric acid, propionic acid, sulfuric acid, tartaric acid, ammoniasolution, ammonium carbonate, diethanolamine, potassium hydroxide,sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide ortrolamine. In certain embodiments, the pharmaceutically acceptable pHadjuster is sodium hydroxide or hydrochloric acid.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein further comprise an osmolarity adjuster. In certainembodiments, the osmolarity adjuster is selected from the groupcomprising sodium chloride, potassium chloride, isosorbide, mannitol,xylitol or any combination thereof. In certain embodiments, theosmolarity adjuster is sodium chloride.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein may further comprise one or more additionalpharmaceutically acceptable carriers, excipients, or diluents. Examplesof liquid carriers for parenteral administration include water, alcohols(including monohydric alcohols and polyhydric alcohols, e.g., glycols)and their derivatives, and oils (e.g., fractionated coconut oil andarachis oil). Examples of such carriers are well known to those skilledin the art and can be prepared in accordance with acceptablepharmaceutical procedures, such as, for example, those described inRemington: The Science and Practice of Pharmacy, 20th edition, ed.Alfonso R. Gennaro (Lippincott Williams & Wilkins, Baltimore, Md.(2000)). For example, liquid media or liquid carriers (which are usedinterchangeably herein) can be used in preparing the liquidpharmaceutical formulations described herein such as solutions,suspensions, and emulsions.

In certain embodiments, the unit liquid pharmaceutical formulationcomprises one of more of water; a pH adjuster; and an osmolarityadjuster. In particular embodiments, the pH adjuster is selected fromthe group consisting of potassium hydroxide, sodium hydroxide,hydrochloric acid, and combinations thereof. In some embodiments, theosmolarity adjuster is selected from the group consisting of sodiumchloride, potassium chloride, and combinations thereof.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein may further comprise other suitable pharmaceuticallyacceptable additives such as solubilizers, emulsifiers, buffers,preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, colors, viscosity regulators, stabilizers, andosmo-regulators.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein further comprise a second therapeutic agent. In certainembodiments, furosemide is the sole therapeutic agent present in theunit liquid pharmaceutical formulations described herein.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein can have an osmolarity in the range of from about 100mOsm/kg to about 1600 mOsm/kg, from about 200 mOsm/kg to about 1600mOsm/kg, from about 400 mOsm/kg to about 1600 mOsm/kg, from about 800mOsm/kg to about 1600 mOsm/kg, from about 1200 mOsm/kg to about 1600mOsm/kg, from about 100 mOsm/kg to about 1200 mOsm/kg, from about 100mOsm/kg to about 800 mOsm/kg, from about 100 mOsm/kg to about 400mOsm/kg, from about 100 mOsm/kg to about 200 mOsm/kg, from about 200mOsm/kg to about 1200 mOsm/kg, from about 200 mOsm/kg to about 800mOsm/kg, from about 200 mOsm/kg to about 400 mOsm/kg, from about 400mOsm/kg to about 1200 mOsm/kg, from about 400 mOsm/kg to about 800mOsm/kg, or from about 800 mOsm/kg to about 1200 mOsm/kg. In someembodiments, the unit liquid pharmaceutical formulations describedherein have an osmolarity in the range of from about 200 mOsm/kg toabout 400 mOsm/kg.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein can have an osmolarity in the range of from about 275mOsm/kg to about 350 mOsm/kg. In certain embodiments, the unit liquidpharmaceutical formulations described herein are isosmotic.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein have a volume of from about 0.05 mL to about 40 mL,from about 0.1 mL to about 40 mL, from about 0.5 mL to about 40 mL, fromabout 1 mL to about 40 mL, from about 2 mL to about 40 mL, from about 5mL to about 40 mL, from about 10 mL to about 40 mL, from about 20 mL toabout 40 mL, from about 0.05 mL to about 20 mL, from about 0.05 mL toabout 10 mL, from about 0.05 mL to about 5 mL, from about 0.05 mL toabout 2 mL, from about 0.05 mL to about 1 mL, from about 0.05 mL toabout 0.5 mL, from about 0.05 mL to about 0.1 mL, from about 0.1 mL toabout 20 mL, from about 0.1 mL to about 10 mL, from about 0.1 mL toabout 5 mL, from about 0.1 mL to about 2 mL, from about 0.1 mL to about1 mL, from about 0.1 mL to about 0.5 mL, from about 0.5 mL to about 20mL, from about 0.5 mL to about 10 mL, from about 0.5 mL to about 5 mL,from about 0.5 mL to about 2 mL, from about 0.5 mL to about 1 mL, fromabout 1 mL to about 20 mL, from about 1 mL to about 10 mL, from about 1mL to about 5 mL, from about 1 mL to about 2 mL, from about 2 mL toabout 20 mL, from about 2 mL to about 10 mL, from about 2 mL to about 5mL, from about 5 mL to about 20 mL, from about 5 mL to about 10 mL, orfrom about 10 mL to about 20 mL. In certain embodiments, the unit liquidpharmaceutical formulations described herein have a volume of from about0.5 mL to about 20 mL. In certain embodiments, the unit liquidpharmaceutical formulations described herein have a volume of from about0.5 mL to about 10 mL.

In various embodiments, the unit liquid pharmaceutical formulationsdescribed herein have a volume of about 0.05 mL, about 0.1 mL, about 0.5mL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL,about 3.5 mL, about 4 mL, about 4.5 mL, about 5 mL, about 6 mL, about 7mL, about 8 mL, about 9 mL, about 10 mL, about 20 mL, or about 40 mL. Incertain embodiments, the unit liquid pharmaceutical formulationsdescribed herein have a volume of about 3.5 mL or about 10 mL.

Methods of Treatment

In one aspect, the liquid pharmaceutical formulations or unit liquidpharmaceutical formulations described herein may be used for thetreatment or prevention of a variety of diseases and disorders such as,but not limited to, congestion, edema, fluid overload, or hypertensionin a patient in need thereof.

In various embodiments, the method comprises administering to thepatient a liquid pharmaceutical formulation described herein, whereinthe liquid pharmaceutical formulation generally comprises:

(i) furosemide, or a pharmaceutically acceptable salt thereof;

(ii) one or more pharmaceutically acceptable excipients; and

(iii) a pharmaceutically acceptable buffer,

wherein the concentration of furosemide in the liquid pharmaceuticalformulation is from about 40 mg/mL to about 250 mg/mL. In certainembodiments, the pH of the liquid pharmaceutical formulation is fromabout 6.5 to about 8.5.

In various embodiments, the method comprises administering to thepatient a unit liquid pharmaceutical formulation described herein,wherein the unit liquid pharmaceutical formulation generally comprises:

(i) from about 10 mg to about 200 mg furosemide, or a pharmaceuticallyacceptable salt thereof;

(ii) one or more pharmaceutically acceptable excipients; and

(iii) a pharmaceutically acceptable buffer.

wherein the concentration of furosemide in the unit liquidpharmaceutical formulation is from about 40 mg/mL to about 200 mg/mL. Incertain embodiments, the pH of the unit liquid pharmaceuticalformulation is from about 6.5 to about 8.5.

In certain embodiments, the liquid pharmaceutical formulation furthercomprises a second therapeutic agent. In some embodiments, the liquidpharmaceutical formulation and the second therapeutic agent areadministered simultaneously, together or separately, or separately atdifferent times, as part of a regimen.

In certain embodiments, the liquid pharmaceutical formulations can beadministered parenterally, including by infusion, injection orimplantation, which includes subcutaneous administration as appropriate.For example, the liquid pharmaceutical formulations can be administeredby, for example, subcutaneous injection or delivery, or intravenousinjection or delivery. In some embodiments, the liquid pharmaceuticalformulation is administered to the patient intravenously. In someembodiments, the liquid pharmaceutical formulation is administered tothe patient by subcutaneous injection or subcutaneous infusion. In someembodiments, the liquid pharmaceutical formulation is administered tothe patient by subcutaneous infusion using an on-body, subcutaneousdelivery system. In some embodiments, the liquid pharmaceuticalformulation is administered to the patient by subcutaneous infusionusing a wearable subcutaneous delivery system. In some embodiments, theliquid pharmaceutical formulation is administered to the patient bysubcutaneous infusion using a pump device. In some embodiments, the pumpdevice is a micropump device or a patch device. In some embodiments, thepump device is a patch device.

In certain embodiments, the liquid pharmaceutical formulation isadministered to the patient by subcutaneous infusion over about 0.5 hrs,about 1.0 hrs, about 1.5 hrs, about 2.0 hrs, about 4.0 hrs, or about 8.0hrs.

In certain embodiments, the unit liquid pharmaceutical formulationfurther comprises a second therapeutic agent. In some embodiments, theunit liquid pharmaceutical formulation and the second therapeutic agentare administered simultaneously, together or separately, or separatelyat different times, as part of a regimen.

In certain embodiments, the unit liquid pharmaceutical formulations canbe administered parenterally, including by infusion, injection orimplantation, which includes subcutaneous administration as appropriate.For example, the unit liquid pharmaceutical formulations can beadministered by, for example, subcutaneous injection or delivery, orintravenous injection or delivery. In some embodiments, the unit liquidpharmaceutical formulation is administered to the patient intravenously.In some embodiments, the unit liquid pharmaceutical formulation isadministered to the patient by subcutaneous injection or subcutaneousinfusion. In some embodiments, the unit liquid pharmaceuticalformulation is administered to the patient by subcutaneous infusionusing an on-body, subcutaneous delivery system. In some embodiments, theunit liquid pharmaceutical formulation is administered to the patient bysubcutaneous infusion using a wearable subcutaneous delivery system. Incertain embodiments, the unit liquid pharmaceutical formulation isadministered to the patient by subcutaneous infusion using a pumpdevice. In some embodiments, the pump device is a micropump device or apatch device. In some embodiments, the pump device is a patch device.

In certain embodiments, the unit liquid pharmaceutical formulation isadministered to the patient by subcutaneous infusion over about 0.5 hrs,about 1 hrs, about 1.5 hrs, about 2 hrs, about 4 hrs, or about 8 hrs.

When administered for the treatment or prevention of a disease ordisorder disclosed herein, it may be understood that an effective dosagecan vary depending upon many factors such as the particular compound ortherapeutic combination utilized, the mode of administration, andseverity of the condition being treated, as well as the various physicalfactors related to the individual being treated. In therapeuticapplications, a liquid pharmaceutical formulation or unit liquidpharmaceutical formulation described herein may be provided to a patientalready suffering from said disease or disorder in an amount sufficientto cure or at least partially ameliorate the symptoms of the disease ordisorder and its complications. The dosage to be used in the treatmentof a specific individual typically must be subjectively determined by anattending physician. The variables involved include the specificcondition and state as well as the size, age and response pattern of thepatient. In some embodiments, the amount sufficient to cure or at leastpartially ameliorate the symptoms of the disease or disorder and itscomplications is an effective amount. In some embodiments, the amountsufficient to cure or at least partially ameliorate the symptoms of thedisease or disorder and its complications is a therapeutically effectiveamount.

Kits

In one aspect, the invention provides kits for the treatment orprevention of a variety of diseases and disorders such as, but notlimited to, congestion, edema, fluid overload, or hypertension in apatient in need thereof.

In various embodiments, a kit comprises a liquid pharmaceuticalformulation described herein. In certain embodiments, the kit comprisesone or more unit doses of the liquid pharmaceutical formulation. Incertain embodiments, the kit further comprises a medical device. Incertain embodiments, the kit further comprises instructions for treatinga disease or disorder of the present invention.

In various embodiments, a kit comprises a unit liquid pharmaceuticalformulation described herein. In certain embodiments, the kit comprisesone or more units of the liquid pharmaceutical formulation. In someembodiments, the kit comprises one, two, three or more units of theliquid pharmaceutical formulation. In certain embodiments, the kitfurther comprises a medical device. In certain embodiments, the kitfurther comprises instructions for treating a disease or disorder of thepresent invention.

A number of medical devices have been proposed to facilitateself-administration of a pharmaceutical formulation. The device mayinclude a reservoir containing, for example, pre-loaded with, the liquidpharmaceutical formulation described herein to be administered. Forexample, a micropump can provide precise subcutaneous administration ofsmall quantities of a liquid pharmaceutical formulation. Such micropumpscan be compact and portable. Another type of device useful forsubcutaneous delivery or administration of pharmaceutical formulationsis often referred to as a patch device, an on-body, subcutaneousdelivery system, or a wearable subcutaneous delivery system (e.g., apump-patch device). Patch devices usually are attached directly to theskin of a patient.

Accordingly, in various embodiments, a medical device such as amicropump or patch device can include a reservoir containing apharmaceutical formulation, a subcutaneous injection needle configuredfor removable insertion into skin of a patient, a micropump having aninlet in fluid communication with the reservoir and an outlet in fluidcommunication with the subcutaneous injection needle, a control systemconfigured for controlling the micropump to deliver the pharmaceuticalformulation from the reservoir to the subcutaneous injection needle,whereby the pharmaceutical formulation is administered subcutaneously toa patient, and a housing for supporting the reservoir, subcutaneousinjection needle, micropump and control system, the housing beingportable and adapted for contact with the skin of the patient. Theliquid pharmaceutical formulation contained within the reservoir can beany of the liquid pharmaceutical formulations or the unit liquidpharmaceutical formulations described herein.

In certain embodiments, the medical device can be of a unitaryconstruction. Such medical devices can be for a single or one-time use.In particular embodiments, the medical device can be of a multi-piececonstruction. In such medical devices, a disposable or a reusableportion or component can be present. For example, a housing defining orincluding the reservoir can be a disposable or a reusable component ofthe medical device. In some embodiments, the disposable or reusablehousing defining or including the reservoir can contain a pharmaceuticalformulation of the present teachings. In various embodiments, thesubcutaneous injection needle can be a disposable component of themedical device.

In certain embodiments, the medical device is a pump device. In someembodiments, the pump device is a micropump device or a patch device. Insome embodiments, the pump device is a patch device. In certainembodiments, the medical device is selected from the group comprising aneedle and syringe set, an autoinjector, a single use fixed doseinjection pen, a multiuse fixed dose injection pen, a single usevariable dose injection pen, or a multiuse variable dose injection pen.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are merely forthe purposes of illustration of certain aspects and embodiments of thepresent invention, and are not intended to limit the invention.

Example 1. Effect of pH on Furosemide Solubility in LiquidPharmaceutical Formulations

The solubility of furosemide was determined in six buffers over apH-range of pH=6.0-8.5 at two buffer strengths (50 and 200 mM). Thetested buffers are found Table 1.

TABLE 1 Buffer Composition for pH Solubility Studies Screening BufferTarget Round # Strength (mM) Buffer Type pH 1 50 Sodium Phosphate 6.07.4 8.5 Potassium Phosphate 6.0 7.4 8.5 Tromethamine/HCl 6.0 7.4 8.5 2200 Histidine/HCl 6.0 7.4 8.5 Citrate* 6.0 7.4 Tromethamine/HCl 6.0 7.48.5 Tromethamine 6.0 7.4 8.5 Sodium Phosphate 6.0 7.4 8.5 PotassiumPhosphate 6.0 7.4 8.5 *A stable pH of 8.5 could not be achieved likelydue to lower buffer pKaExperimental Setup:

Solid furosemide (approx. 100 mg) was added to buffer solutions (2 mL)until the mixture became saturated (approx. 50 mg/mL).

Screening I: pH was adjusted upon preparation and at each time pointusing base (NaOH, 1 M).

Screening II: Solubility was assisted by sonication (20 min) uponinitial preparation and then pH was adjusted (only after sonication)using base (NaOH, 1 M or 12 M).

Samples were tumbled for 48 hours under ambient conditions and protectedfrom light.

At t=2 h, t=24 h, and t=48 h, solids were removed from the samples bycentrifugation and the supernatants were tested for appearance, pH,osmolarity, and recovery (HPLC assay).

Results:

The results of the experiments are captured in Table 2 and Table 3.

TABLE 2 Results from Solubility Studies (Screening I) Average AveragePeak Buffer Type Target pH Time Point RT [min] Area [mAu] Apparent pH~50 mM 6.0 t2 h 9.43 22197 6.10 Sodium t24 h 9.62 345032 6.17 Phosphatet48 h 9.57 336909 6.38 7.4 t2 h 9.42 1782711 6.90 t24 h 9.40 26764326.90 t48 h 9.58 2501189 7.01 8.5 t2 h 9.45 2376815 6.90 t24 h 9.523117374 6.90 t48 h 9.47 3342401 7.01 ~50 mM 6.0 t2 h 9.49 261577 6.10Potassium t24 h 9.50 290867 6.11 Phosphate t48 h 9.52 256901 6.19 7.4 t2h 9.45 2066328 6.80 t24 h 9.55 2788914 6.95 t48 h 9.60 2558554 7.04 8.5t2 h 9.52 3380843 6.90 t24 h 9.37 4673867 7.05 t48 h 9.63 3634968 7.06~50 mM 6.0 t2 h 9.60 73912 6.20 Tromethamine/ t24 h 9.44 219362 5.80 HClt48 h 9.55 254334 6.07 7.4 t2 h 9.57 1589821 6.80 t24 h 9.44 22017426.80 t48 h 9.44 1767996 6.80 8.5 t2 h 9.64 4080795 7.00 t24 h 9.375061242 7.13 t48 h 9.55 4359878 6.99 Average c(furosemide) Stdev RSDRecovery Osmolarity Buffer Type Appearance [mg/mL] [mg/mL] [%] [%]a[mOsm/Kg] ~50 mM Very cloudy 0.02 0.00 19.2* 100 212 Sodium Cloudy 2.700.24 9.0* 11415 118 Phosphate Cloudy 3.06 0.63 20.5* 12945 141 Cloudy17.17 0.71 4.1 100 232 Cloudy 25.65 1.02 4.0 149 233 Cloudy 23.96 1.114.6 139 237 Slightly 22.76 0.62 2.7 100 241 cloudy Slightly 29.53 0.923.1 130 242 cloudy Slightly 32.01 0.83 2.6 141 276 cloudy ~50 mM Verycloudy 2.33 0.02 0.9 100 108 Potassium Cloudy 2.77 0.09 3.2 119 105Phosphate Cloudy 2.43 0.04 1.5 104 115 Cloudy 19.76 0.29 1.5 100 193Cloudy 26.73 1.00 3.7 135 190 Cloudy 24.51 0.56 2.3 124 213 Slightly32.45 1.26 3.9 100 265 cloudy Slightly 44.94 2.88 6.4 138 255 cloudySlightly 40.76 0.66 1.6 126 283 cloudy ~50 mM Very cloudy 0.52 0.02 3.0100 124 Tromethamine/ Cloudy 1.92 0.04 2.2 371 129 HCl Cloudy 2.37 0.104.3 457 133 Cloudy 15.16 0.30 2.0 100 165 Cloudy 21.07 0.28 1.3 139 181Cloudy 16.88 1.59 9.4 111 186 Slightly 39.21 0.99 2.5 100 242 cloudySlightly 48.68 1.76 3.6 124 239 cloudy Slightly 44.24 3.78 8.5 113 258cloudy aRecovery [%]= set to 100 for t_(2 h). *Measurement obtained fromduplicate analysis.

TABLE 3 Results from Solubility Studies (Screening II) Average AveragePeak Buffer Type Target pH Time Point RT [min] Area [mAu] Apparent pH200 mM 6.0 t2 h 11.82 374540 6.1 Histidine/HCl t24 h 11.39 191961 6.2t48 h 11.42 173725 6.2 7.4 t2 h 11.61 2284085 7.6 t24 h 11.41 19178267.6 t48 h 11.42 957586 7.6 8.5 t2 h 11.63 1789646 8.6 t24 h 11.421615857 8.6 t48 h 11.42 871724 8.6 200 mM 6.0 t2 h 11.76 426896 6.1Citrate t24 h 11.41 119426 6.1 t48 h 11.44 86361 6.1 7.4 t2 h 11.671063430 7.6 t24 h 11.38 691059 7.4 t48 h 11.42 388579 7.4 200 mM 6.0 t2h 11.75 626638 6.1 Tromethamine/ t24 h 11.42 194823 6.1 HCl t48 h 11.42231207 6.2 7.4 t2 h 11.72 2552568 7.0 t24 h 11.43 2020974 7.0 t48 h11.42 2025794 7.0 8.5 t2 h 11.71 4020943 8.8 t24 h 11.44 3021911 8.3 t48h 11.43 2009714 8.6 200 mM 6.0 t2 h 11.93 1279330 6.1 Tromethamine t24 h11.44 217301 6.3 t48 h 11.44 215822 6.2 7.4 t2 h 11.82 3578860 7.6 t24 h11.44 2711852 7.6 t48 h 11.43 2717488 7.6 8.5 t2 h 11.83 3258887 8.7 t24h 11.43 2736373 8.7 t48 h 11.43 2770650 8.7 200 mM 6.0 t2 h 11.44 1105435.9 Sodium t24 h 11.42 134417 5.9 Phosphate t48 h 11.42 144645 6.2 7.4t2 h 11.43 629428 7.5 t24 h 11.43 733746 7.2 t48h 11.42 957966 7.3 8.5t2 h 11.41 586353 8.6 t24 h 11.43 694568 8.6 t48 h 11.42 964511 8.4 200mM 6.0 t2 h 11.42 110247 5.8 Potassium t24 h 11.42 120065 6.2 Phosphatet48 h 11.41 136073* 6.1 7.4 t2 h 11.43 1255655 7.2 t24 h 11.42 17491767.4 t48 h 11.42 2255569 7.4 8.5 t2 h 11.41 1082568 8.4 t24 h 11.421492050 8.6 t48 h 11.41 2085497 8.7 Average c(furosemide) Stdev RecoveryOsmolarity Buffer Type Appearance [mg/mL] [mg/mL] % RSD [%]a [mOsm/kg]200 mM Very Cloudy BLQ NA NA NA 441 Histidine/HCl Very Cloudy 2.81 0.020.7 NA 392 Very Cloudy 2.54 0.00 0.1 NA 477 Cloudy 25.49 0.61 2.4 100588 Cloudy 28.42 0.07 0.2 111 584 Cloudy 14.14 0.05 0.4 55 616 Slightly18.76 0.15 0.8 100 553 Cloudy Slightly 23.94 0.12 0.5 128 558 CloudyCloudy 12.87 0.03 0.2 69 678 200 mM Very Cloudy 0.21 0.01 2.9 100 516Citrate Very Cloudy 1.74 0.01 0.7 829 533 Very Cloudy 1.25 0.00 0.1 595557 Cloudy 8.89 0.11 1.2 100 488 Cloudy 10.22 0.03 0.3 115 484 Cloudy5.73 0.03 0.5 64 549 200 mM Very Cloudy 2.62 0.11 4.4 100 121Tromethamine/ Very Cloudy 2.86 0.00 0.2 109 114 HCl Very Cloudy 3.470.01 0.2 132 127 Cloudy 29.14 0.27 0.9 100 232 Cloudy 29.95 0.11 0.4 103215 Cloudy 29.85 0.10 0.2 102 233 Slightly 50.92 2.44 7.3 100 177 CloudySlightly 44.80 0.07 0.2 88 257 Cloudy Cloudy 29.61 0.54 0.2 58 252 200mM Very Cloudy 11.93 0.05 0.4 100 403 Tromethamine Very Cloudy 3.19 0.020.5 27 406 Very Cloudy 3.24 0.00 0.1 27 446 Slightly 43.09 1.99 4.6 100434 Cloudy Slightly 40.20 0.08 0.2 93 481 Cloudy Slightly 40.01 0.11 0.393 482 Cloudy Slightly 38.89 0.16 0.4 100 403 Cloudy Slightly 40.56 0.070.2 104 347 Cloudy Slightly 40.79 0.66 1.6 105 433 Cloudy 200 mM VeryCloudy 1.70 0.02 0.9 100 388 Sodium Very Cloudy 2.00 0.04 2.0 118 399Phosphate Cloudy 2.15 0.02 1.0 126 393 Cloudy 9.32 0.13 1.4 100 330Cloudy 10.79 0.16 1.5 116 310 Slightly 14.08 0.08 0.5 151 310 CloudyCloudy 8.69 0.08 1.0 100 282 Cloudy 10.21 0.04 0.4 117 267 Slightly14.17 0.25 1.7 163 285 Cloudy 200 mM Very Cloudy 1.69 0.02 1.0 100 384Potassium Very Cloudy 1.79 0.01 0.3 106 383 Phosphate Cloudy 2.02* 0.04*1.86* 120* 376 Cloudy 18.53 0.05 0.3 100 462 Cloudy 25.68 0.23 0.9 139471 Slightly 33.11 0.23 0.7 179 481 Cloudy Cloudy 15.98 0.09 0.6 100 487Cloudy 21.91 0.45 2.0 137 497 Slightly 30.62 0.45 1.5 192 423 CloudyaRecovery [%] = set to 100 for t_(2 h). *Measurement obtained fromduplicate analysis. BLQ = Below the limit of quantification.

Solubilities were determined to be dependent on buffer type (at higherbuffer strengths) and were observed to increase at increasing pH values.

pH Screening Round I

The solubility of furosemide was initially determined in sodiumphosphate, potassium phosphate, and tromethamine/HCl buffers at aconcentration of 50 mM.

A significant pH shift was observed for test samples at pH≥7.4 over thecourse of 48 h due to the API. This shift was observed at each timepoint indicating slow dissolution rates of furosemide in the buffermedia.

Maximum equilibrium solubilities could not be determined for pH 7.4 and8.5 due to the pH being shifted to approx. pH=7 (API shift). No pHshifts were observed at pH=6.0.

Generally, solubilities were observed to increase at higher pH values.Furosemide showed highest solubilities of approx. 40 mg/mL. All buffertypes appeared to produce similar solubilities.

All samples were observed to be hypotonic, with osmolarity increasing athigher pHs due to increased furosemide solubility.

pH Screening Round II

The pH-solubility of furosemide was determined at an increased bufferstrength of 200 mM, in the previous buffers along with Histidine/HCl,Citrate, and Tromethamine over a pH-range of pH=6.0-8.5. Additionally,test samples were sonicated prior to pH adjustment to aid APIdissolution and minimize pH shifts throughout the studies.

Only small pH shifts (0.4 pH unit) were observed throughout the studieslikely due to the increased buffer strength and the initial sonicationthat increase dissolution rates.

Super-saturation, likely induced by sonication, was observed at t=2 hand t=24 h for certain buffers.

All test buffers produced low solubilities at pH=6.0 and were shown tosupport solubilities of 8 mg/mL at higher pHs.

Potassium phosphate appeared to produce higher solubilities (2-fold)than sodium phosphate at higher pHs.

Tromethamine based buffers produced the greatest solubility at higherpHs (approx. 40 mg/mL).

Generally, increasing API concentrations correlated with increasingosmolarity values. Some deviations from this trend are reported for thesodium phosphate test solutions.

Example 2. Effect of Excipients on Furosemide Solubility in LiquidPharmaceutical Formulations

The solubility of Furosemide was determined in vehicles designed tocover a formulation space of excipients (single or mixtures) that areregarded as GRAS/safe and are compatible for subcutaneousadministration. Informed by the pH solubility studies, tromethamine wasselected as the lead buffer component. A summary overview of theperformed screenings is given in Table 4.

TABLE 4 Overview of Excipient Solubility Studies Study #Purpose/Objective 1 Excipient solubility (48 h) Target c(furosemide) =100 mg/mL Test solutions: single excipients in neat or aqueous solutions(non-buffered) Excipients: NMP, benzyl alcohol, ethanol, glycerin, PEG3350, PG, Tween 80, PVP K12, β-cyclodextrin pH = 7.4 2 Excipientsolubility (48 h) Target c(furosemide) = 100 mg/mL Test solutions:single excipients in neat or aqueous solutions (non-buffered and nopH-adjustment) Excipients: NMP, benzyl alcohol, ethanol, glycerin, PEG3350, PG, Tween 80, PVP K12, β-cyclodextrin 3 Excipient solubility (48h) Target c(furosemide) = 100 mg/mL Test solutions: single excipients inbuffered solutions Excipients: NMP, benzyl alcohol, ethanol, glycerin,PEG 3350, PG, Tween 80, PVP K12, β-cyclodextrin Buffer strength: 100 mMTromethamine pH: 7.4 4 DOE Full Factorial Study (48 h) Targetc(furosemide) = 150 mg/mL Test solutions: excipients (single andmixtures) in buffered solutions Excipients: NMP and benzyl alcoholBuffer strengths: 50 and 100 mM Tromethamine pH: 7.4 5 ExcipientSolubility (48 h) Target c(furosemide) = 100 mg/mL Test solutions:single excipients in buffered solutions Excipients: NMP, benzyl alcohol,glycerin and PEG 3350 Buffer strengths: 100 mM Tromethamine pH: 6.0 6Excipient Solubility (48 h) Target c(furosemide) = 300 mg/mL Testsolutions: excipients mixture in buffered solutions Excipients: NMP andbenzyl alcohol Buffer strength: 100 mM Tromethamine pH: 4.0, 5.0, 6.0,7.4Experimental Setup:

Solid furosemide was added to buffer solutions (2 mL) until the mixturebecame saturated. Solubility was assisted by sonication (20 min) uponinitial preparation and then pH was adjusted (only after sonication)using base (NaOH, 12 M).

Samples were tumbled for 48 hours at ambient conditions and protectedfrom light.

At t=2 h, t=24 h, and t=48 h, solids were removed from the samples bycentrifugation and the supernatants were tested for appearance, pH,osmolarity, and recovery (HPLC assay).

Results:

The results of the experiments are captured in Table 5, Table 6, Table 7and Table 8.

Solubilities for studies I and II could not be determined due to low pHsvalues and significant pH shifts.

TABLE 5 Results from Excipient Solubility Studies (Study 3) VehicleAverage Composition Average Peak (pH 7.4) Time Point RT [min] Area [mAu]Apparent pH Appearance 100 mM t2 h 11.40 1825515 7.1 Cloudy Tromethaminet24 h 11.81 1786669 7.8 Cloudy (Control) t48 h 11.82 1749022 7.6 Cloudy100 mM t2 h 11.41 1877232 7.5 Cloudy Tromethamine t24 h 11.81 18319287.9 Cloudy 5% Ethanol t48 h 11.81 1818127 7.9 Cloudy 100 mM t2 h 11.422718702 7.7 Slightly Tromethamine, Cloudy 2% Benzyl Alcohol t24 h 11.812698375 7.7 Slightly Cloudy t48 h 11.82 2681230 7.7 Slightly Cloudy 100mM t2 h 11.41 2310442 7.1 Cloudy Tromethamine, t24 h 11.82 2266515 7.8Cloudy 20% Glycerin t48 h 11.83 2261250 7.8 Cloudy 100 mM t2 h 11.403029623 7.4 Clear Tromethamine, t24 h 11.82 3128866 7.8 Clear 20%N-Methyl- t48 h 11.83 3108641 7.8 Clear pyrrolidone 100 mM t2 h 11.402481519 7.4 Slightly Tromethamine, Cloudy 4% Polyethylene t24 h 11.812456383 7.9 Slightly Glycol 3350 Cloudy t48 h 11.82 2387681 7.5 SlightlyCloudy 100 mM t2 h 11.40 2049508 7.6 Cloudy Tromethamine, 1% t24 h 11.821962976 7.5 Cloudy Propylene Glycol t48 h 11.82 1951402 7.8 Cloudy 100mM t2 h 11.40 1900447 7.8 Cloudy Tromethamine, 0.3% t24 h 11.81 18531248.1 Cloudy Polysorbate 80 t48 h 11.82 1836260 7.5 Cloudy 100 mM t2 h11.40 2230107 7.6 Cloudy Tromethamine, 2% t24 h 11.81 2239373 7.9 VeryCloudy Providone K12 t48h 11.83 2193443 8.0 Very Cloudy 100 mM t2 h11.40 2007575 7.2 Cloudy Tromethamine, t24 h 11.83 1967418 7.8 Cloudy 1%β-Cyclodextrin t48 h 11.82 1934515 7.6 Cloudy Vehicle AverageComposition c[furosemide] Stdev Recovery Osmolality (pH 7.4) (mg/mL)[mg/mL] RSD [%] [%] [mOsm/kg] 100 mM 53.53 0.85 1.59 100 297Tromethamine 50.43 0.09 0.18 94 272 (Control) 48.93 0.29 0.59 91 279 100mM 55.07 1.15 2.1 100 1163 Tromethamine 51.72 0.43 0.8 94 1173 5%Ethanol 50.87 0.45 0.9 92 1159 100 mM 80.13 0.18 0.2 100 454Tromethamine, 2% 76.32 0.23 0.3 95 450 Benzyl Alcohol 75.15 0.54 0.7 94449 100 mM 67.97 0.49 0.7 100 Out of Range Tromethamine, 20% 64.06 0.130.2 94 Out of Range Glycerin 63.34 0.48 0.8 93 Out of Range 100 mM 89.390.50 0.6 100 Out of Range Tromethamine, 20% 88.54 0.97 1.1 99 Out ofRange N-Methyl- 87.17 0.63 0.7 98 Out of Range pyrrolidone 100 mM 73.070.22 0.3 100 404 Tromethamine, 4% 69.45 0.09 0.1 95 387 PolyethyleneGlycol 66.89 0.78 1.2 92 394 3350 100 mM 60.20 0.24 0.4 100 433Tromethamine, 1% 55.44 0.38 0.7 92 414 Propylene Glycol 54.62 0.39 0.791 421 100 mM 55.77 1.29 2.3 100 304 Tromethamine, 0.3% 52.32 0.28 0.594 334 Polysorbate 80 51.38 0.98 1.9 92 336 100 mM 65.58 0.29 0.4 100350 Tromethamine, 2% 63.29 0.55 0.9 97 307 Providone K12 61.43 0.70 1.194 284 100 mM 58.96 0.19 0.3 100 290 Tromethamine, 1% 55.56 0.32 0.6 94274 β-Cyclodextrin 54.15 0.38 0.7 92 278 aRecovery [%] = set to 100t_(2 h).

TABLE 6 Results from Excipient Solubility Studies (Study 4) VehicleAverage Composition Average Peak (pH 7.4) Time Point RT [min] Area [mAu]Apparent pH Appearance 50 mM t2 h 11.39 3031917 7.4 Cloudy Tromethamine,t24 h 11.40 2888759 7.3 Cloudy 5% NMP t48 h 11.42 2787244 7.4 Cloudy 50mM t2 h 11.39 4182448 7.1 Clear Tromethamine, t24 h 11.41 4154858 7.1Clear 20% NMP t48 h 11.41 4118507 6.8 Clear 50 mM t2 h 11.38 3728344 7.3Cloudy Tromethamine, t24 h 11.41 3696317 7.3 Slightly 5% NMP, 2% CloudyBenzyl Alcohol t48 h 11.42 3572812 7.3 Slightly Cloudy 50 mM t2 h 11.404170808 7.3 Clear Tromethamine, t24 h 11.41 4164340 7.4 Clear 20% NMP,2% t48 h 11.41 4152066 7.4 Clear Benzyl Alcohol 100 mM t2 h 11.403128302 7.4 Cloudy Tromethamine, t24 h 11.41 3118246 7.3 Slightly 5% NMPCloudy t48 h 11.42 3006231 7.3 Slightly Cloudy 100 mM t2 h 11.39 41301077.4 Clear Tromethamine, t24 h 11.40 4116277 7.3 Clear 20% NMP t48 h11.41 4112130 7.4 Clear 100 mM t2h 11.41 4121812 7.4 Clear Tromethamine,t24h 11.42 3969948 7.4 Clear 5% NMP, 2% t48h 11.41 3896373 7.4 SlightlyBenzyl Alcohol Cloudy 100 mM t2 h 11.40 4094348 7.5 Clear Tromethamine,t24 h 11.41 4096567 7.3 Clear 20% NMP, 2% t48 h 11.41 4071543 7.4 ClearBenzyl Alcohol 75 mM t2 h 11.40 4160110 7.4 Clear Tromethamine, t24 h11.42 4025902 7.4 Clear 12.5% NMP, 1% t48 h 11.41* 4421340* 7.4 ClearBenzyl Alcohol Vehicle Average Composition c(furosemide) Stdev RecoveryOsmolality (pH 7.4) [mg/mL] [mg/mL] RSD [%] [%]a [mOsm/kg] 50 mM 86.721.44 1.66 100 706 Tromethamine, 82.58 1.10 1.33 95 709 5% NMP 79.65 1.211.52 92 671 50 mM 119.94 0.37 0.3 100 Out of Range Tromethamine, 119.140.41 0.3 99 Out of Range 20% NMP 118.09 0.25 0.2 98 Out of Range 50 mM106.83 1.80 1.7 100 760 Tromethamine, 105.90 0.29 0.3 99 774 5% NMP, 2%102.34 0.74 0.7 96 782 Benzyl Alcohol 50 mM 119.60 2.49 2.1 100 Out ofRange Tromethamine, 119.42 0.85 0.7 100 Out of Range 20% NMP, 2% 120.951.77 1.5 101 Out of Range Benzyl Alcohol 100 mM 89.50 2.01 2.2 100 786Tromethamine, 89.21 0.26 0.3 100 752 5% NMP 87.42 0.58 0.7 98 754 100 mM118.43 0.23 0.2 100 Out of Range Tromethamine, 118.03 0.92 0.8 100 Outof Range 20% NMP 119.79 1.42 1.2 101 Out of Range 100 mM 118.19 0.32 0.3100 848 Tromethamine, 113.80 0.58 0.5 96 875 5% NMP, 2% 113.47 0.53 0.596 875 Benzyl Alcohol 100 mM 117.40 0.24 0.2 100 Out of RangeTromethamine, 117.46 1.14 1.0 100 Out of Range 20% NMP, 2% 118.60 0.980.8 101 Out of Range Benzyl Alcohol 75 mM 119.30 0.24 0.2 100 1587Tromethamine, 115.42 4.32 3.7 97 1576 12.5% NMP, 1% 128.83* 4.73* 3.7*108* 1590 Benzyl Alcohol aRecovery [%] = set to 100 for t_(2 h).*Measurement obtained from duplicate analysis.

TABLE 7 Results from Excipient Solubility Studies (Study 5) AverageAverage Peak Vehicle (pH 6.0) Time Point RT [min] Area [mAu] Apparent pHAppearance 100 mM t2 h 11.41 143472 6.2 Very Cloudy Tromethamine, t24 h11.42 141460 5.8 Very Cloudy 2% Benzyl t48 h 11.39 146503 5.8 VeryCloudy Alcohol 100 mM t2 h 11.41 151028 5.9 Very Cloudy Tromethamine,t24 h 11.42 152347 6.1 Very Cloudy 4% PEG 3350 t48 h 11.40 154068 5.8Very Cloudy 100 mM t2 h 11.42 114569 6.1 Very Cloudy Tromethamine, t24 h11.41 115134 6.1 Very Cloudy 20% Glycerin t48 h 11.40 115883 5.7 VeryCloudy 100 mM t2 h 11.42 346422 6.1 Very Cloudy Tromethamine, t24 h11.42 346383 6.1 Very Cloudy 20% NMP t48 h 11.39 346516 5.6 Very CloudyAverage c[furosemide] Stdev Recovery Osmolality Vehicle (pH 6.0) (mg/mL)[mg/mL] RSD [%] [%] [mOsm/kg] 100 mM 4.08 0.04 0.98 100 393Tromethamine, 4.06 0.03 0.77 99 401 2% Benzyl 4.15 0.07 1.69 102 394Alcohol 100 mM 4.32 0.03 0.7 100 270 Tromethamine, 4.40 0.03 0.6 102 2724% PEG 3350 4.38 0.01 0.2 102 268 100 mM 3.17 0.06 1.9 100 Out of RangeTromethamine, 3.23 0.05 1.6 102 Out of Range 20% Glycerin 3.18 0.05 1.6100 Out of Range 100 mM 10.50 0.06 0.6 100 Out of Range Tromethamine,10.53 0.12 1.2 100 Out of Range 20% NMP 10.48 0.06 0.6 100 Out of RangeaRecovery [%] = set to 100 for t_(2 h).

TABLE 8 Results from Excipient Solubility Studies (Study 6) AverageAverage Peak Vehicle Time Point RT [min] Area [mAu] Apparent pHAppearance 100 mM t2 h 11.43 12584 3.9 Very Cloudy Tromethamine t24 h11.41* 12008* 3.6 Very Cloudy pH = 4.0, 25% t48 h 11.42* 39411* 4.7 VeryCloudy NMP, 2% Benzyl Alcohol 100 mM t2 h 11.43 59108 5.0 Very CloudyTromethamine t24 h 11.42 57529 4.6 Very Cloudy pH 5.0, 25% t48 h 11.4292084 5.1 Very Cloudy NMP, 2% Benzyl Alcohol 100 mM t2 h 11.42 5997116.0 Very Cloudy Tromethamine t24 h 11.42 606643 5.8 Very Cloudy pH 6.0,25% t48 h 11.42 614155 6.1 Very Cloudy NMP, 2% Benzyl Alcohol 100 mM t2h 11.43 6752752 7.3 Cloudy Tromethamine t24 h 11.43 7144685 7.3 CloudypH 7.4, 25% t48 h 11.43 6669530 7.0 Cloudy NMP, 2% Benzyl AlcoholAverage c(furosemide) Stdev Recovery Osmolality Vehicle [mg/mL] [mg/mL]RSD [%] [%] [mOsm/kg] 100 mM BLQ NA NA NA Out of Range Tromethamine BLQ*NA NA NA Out of Range pH = 4.0, 25% 0.75* 0.09* 11.8* NA* Out of RangeNMP, 2% Benzyl Alcohol 100 mM 1.34 0.05 3.5 100 Out of RangeTromethamine 1.35 0.05 3.5 101 Out of Range pH 5.0, 25% 2.42 0.02 0.9181 Out of Range NMP, 2% Benzyl Alcohol 100 mM 18.42 0.09 0.5 100 Out ofRange Tromethamine 18.74 0.13 0.7 102 Out of Range pH 6.0, 25% 18.940.10 0.5 103 Out of Range NMP, 2% Benzyl Alcohol 100 mM 212.77 1.74 0.8100 Out of Range Tromethamine 225.86 4.37 1.9 106 Out of Range pH 7.4,25% 210.51 1.27 0.6 99 Out of Range NMP, 2% Benzyl Alcohol aRecovery [%]= set to 100 for t_(2 h). *Measurement obtained from duplicate analysis.Excipient Solubility Studies (Studies 1 and 2)

An attempt was made to determine the solubility of furosemide innon-buffered excipients solutions adjusted to pH of 7.4 using a strongbase (NaOH). Solubilities could not be determined due to the pH notbeing stable upon sample preparation (Study 1).

An attempt was made to determine furosemide solubility in excipientssolutions without pH adjustment. All test samples displayed very lowsolubilities (below the limit of quantification) likely due to the lowpHs driven by the API's pKa.

Excipient Solubility Studies (Study 3)

The solubility of furosemide was determined in excipient bufferedsolutions (tromethamine) at a pH of 7.4. N-methyl-pyrrolidone (NMP, 20%)reported the highest solubility (approx. 87 mg/mL) that was maintainedover the course of 48 h. Maximum solubilities could not be determined assaturation was never achieved.

A pH variability (up to 0.7 pH units) was observed for certainconditions throughout the studies.

Benzyl alcohol (BA, 2%), glycerin (20%) and polyethylene glycol (4%)resulted in the highest furosemide solubilities (approx. 60-75 mg/mL)that were maintained over the course of 48 h.

Osmolarities could not be accurately measured due to organic content insome formulations.

Excipient Solubility Studies (Study 4)

A full factorial DOE study was performed to determine the optimalamounts of NMP, benzyl alcohol and buffer (tromethamine) required toproduce the highest solubility. Any potential synergistic effectsstemming from various excipient combinations were also investigated.

A small pH variability (up to 0.3 pH units) was observed throughout thestudies.

Highest solubility (>120 mg/mL) was always achieved at higher NMPconcentrations (20%).

Minimum concentrations of 5% NMP in combination with 2% benzyl alcoholwere reported to produce a solubility >100 mg/mL.

Furosemide solubility was observed to be highest at high amounts of NMPand BA and was relatively unaffected by buffer strength.

At low NMP levels, higher buffer concentration appeared to produceslightly higher solubilities.

The effect of NMP was stronger at low BA levels and the effect of BA wasstronger at low NMP levels. Both are co-solvents and likely dissolvefurosemide by the same mechanism.

Osmolarities could not be properly measured due to the organic contentof the test vehicles.

Excipient Solubility Studies (Study 5)

The solubility of furosemide was determined in excipient bufferedsolutions (tromethamine) at pH 6.0.

A small pH variability (up to 0.4 pH units) was observed throughout thestudies.

Solubilities ranged from approximately 3-10 mg/mL. N-Methyl-pyrrolidone(20%) yielded the highest solubility (approx. 10 mg/mL) that wasmaintained over the course of 48 h.

All solutions appeared cloudy indicating saturation of each solution.

Osmolarities could not be properly measured due to the organic contentof the test vehicles.

Excipient Solubility Studies (Study 6)

The solubility of furosemide was determined in excipient bufferedsolutions (N-methyl-pyrrolidone, benzyl alcohol, tromethamine) at pH's4.0, 5.0, 6.0, and 7.4.

A pH variability of 0.7 units was observed for pH 4.0 test samples.

Solubility significantly increased between pH 6-7.4. The maximumobserved solubility of furosemide was approximately 210 mg/mL at pH 7.4.

All solutions appeared cloudy indicating solution saturation. Testsamples appeared to increase in viscosity at higher concentrations(around 200 mg/mL).

Osmolarities could not be properly measured due to the organic contentof the test vehicles.

Example 3. Manufacturing Process for a Furosemide Liquid Formulation(107 mg/mL Furosemide, 50 mM Tromethamine, 10% (w/v)N-methyl-pyrrolidone, 2% (w/v) Benzyl Alcohol)

In the following example, the manufacturing process for preparing a 107mg/mL furosemide liquid formulation is described.

30.5 g tromethamine (USP), 500.5 g N-methyl-pyrrolidone (USP) and 100.0g benzyl alcohol (USP) were weighed and added to a 5 L volumetric flask.To this, approximately 2.5 L of ultra-pure water was added and thenstirred using a magnetic stirrer bar. Once the solid materials haddissolved 537.5 g furosemide (USP) was added, producing a suspension.After approximately 30 minutes of additional stirring the pH of thesuspension/solution was adjusted to 7.4 using a 10N sodium hydroxidesolution (˜181.0 mL 10N sodium hydroxide solution required). Stirringwas continued for a further 30 minutes after which the volume of thesolution was made to volume using ultra-pure water. Finally, the pH ofthe solution was verified and found to be 7.5.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The disclosure may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the disclosure described herein. Scope of thedisclosure is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed:
 1. A liquid pharmaceutical formulation comprising:furosemide, or a pharmaceutically acceptable salt thereof, wherein theconcentration of furosemide is from about 60 mg/mL to about 120 mg/mL;benzyl alcohol, wherein the amount of benzyl alcohol is from about 0.5%(w/w) to about 5% (w/w); and a pharmaceutically acceptable buffercomprising tromethamine or a pharmaceutically acceptable salt thereof,wherein the concentration of tromethamine is from about 25 mM to about150 mM; wherein the liquid pharmaceutical formulation has a pH ofbetween about 6.5 to about 8.5, and is isosmotic.
 2. The liquidpharmaceutical formulation of claim 1, wherein the concentration offurosemide is from about 60 mg/mL to about 100 mg/mL.
 3. The liquidpharmaceutical formulation of claim 1, wherein the concentration offurosemide is from about 70 mg/mL to about 90 mg/mL.
 4. The liquidpharmaceutical formulation of claim 1, wherein the amount of benzylalcohol is from about 1% (w/w) to about 3.5% (w/w).
 5. The liquidpharmaceutical formulation of claim 1, wherein the concentration oftromethamine is from about 50 mM to about 125 mM.
 6. The liquidpharmaceutical formulation of claim 1, wherein the liquid pharmaceuticalformulation has a pH of between about 7 to about 8.5.
 7. The liquidpharmaceutical formulation of claim 1, wherein the liquid pharmaceuticalformulation has a pH of between about 7 to about
 8. 8. A liquidpharmaceutical formulation comprising: furosemide, or a pharmaceuticallyacceptable salt thereof, wherein the concentration of furosemide is fromabout 70 mg/mL to about 100 mg/mL; benzyl alcohol, wherein the amount ofbenzyl alcohol is from about 1% (w/w) to about 3.5% (w/w); and apharmaceutically acceptable buffer comprising tromethamine or apharmaceutically acceptable salt thereof, wherein the concentration oftromethamine is from about 50 mM to about 125 mM; wherein the liquidpharmaceutical formulation has a pH of between about 7 to about 8.5, andis isosmotic.
 9. The liquid pharmaceutical formulation of claim 8,wherein the concentration of furosemide is about 80 mg/mL to 100 mg/mL.10. The liquid pharmaceutical formulation of claim 8, wherein theconcentration of furosemide is about 80 mg/mL.
 11. The liquidpharmaceutical formulation of claim 8, wherein the liquid pharmaceuticalformulation has a pH of between about 7.5 to about 8.5.
 12. The liquidpharmaceutical formulation of claim 8, wherein the liquid pharmaceuticalformulation has a pH of between about 7 to about
 8. 13. A liquidpharmaceutical formulation comprising: furosemide, or a pharmaceuticallyacceptable salt thereof, wherein the concentration of furosemide is fromabout 80 mg/mL to about 100 mg/mL; benzyl alcohol, wherein the amount ofbenzyl alcohol is from about 1% (w/w) to about 3.5% (w/w); and apharmaceutically acceptable buffer comprising tromethamine or apharmaceutically acceptable salt thereof, wherein the concentration oftromethamine is from about 50 mM to about 125 mM; wherein the liquidpharmaceutical formulation has a pH of between about 7 to about 8, andis isosmotic.
 14. The liquid pharmaceutical formulation of claim 13,wherein the concentration of furosemide is about 80 mg/mL.
 15. Theliquid pharmaceutical formulation of claim 13, wherein the concentrationof tromethamine is about 50 mM to 100 mM.
 16. The liquid pharmaceuticalformulation of claim 14, wherein the concentration of tromethamine isabout 50 mM to 100 mM.
 17. The liquid pharmaceutical formulation ofclaim 13, wherein the concentration of tromethamine is about 75 mM to125 mM.
 18. The liquid pharmaceutical formulation of claim 14, whereinthe concentration of tromethamine is about 75 mM to 125 mM.
 19. Theliquid pharmaceutical formulation of claim 13, further comprising one ormore of water, an osmolarity adjuster, and a pH adjuster.
 20. The liquidpharmaceutical formulation of claim 14, further comprising one or moreof water, an osmolarity adjuster, and a pH adjuster.
 21. The liquidpharmaceutical formulation of claim 13, wherein isosmotic is anosmolarity in the range of about 275 mOsM to about 350 mOsM.
 22. Theliquid pharmaceutical formulation of claim 13, wherein isosmotic is anosmolality in the range of about 275 mOsm/kg to about 350 mOsm/kg.